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Background: Deficits in psychosocial functioning are present in the early stages of psychosis. Several factors, such as premorbid adjustment, neurocognitive performance, and cognitive reserve (CR), potentially influence functionality. Sex differences are observed in individuals with psychosis in multiple domains. Nonetheless, few studies have explored the predictive factors of poor functioning according to sex in first-episode psychosis (FEP). This study aimed to explore sex differences, examine changes, and identify predictors of functioning according to sex after onset., Materials and Methods: The initial sample comprised 588 individuals. However, only adults with non-affective FEP ( n = 247, 161 males and 86 females) and healthy controls ( n = 224, 142 males and 82 females) were included. A comprehensive assessment including functional, neuropsychological, and clinical scales was performed at baseline and at 2-year follow-up. A linear regression model was used to determine the predictors of functioning at 2-year follow-up., Results: FEP improved their functionality at follow-up (67.4% of both males and females). In males, longer duration of untreated psychosis (β = 0.328, p = 0.003) and worse premorbid adjustment (β = 0.256, p = 0.023) were associated with impaired functioning at 2-year follow-up, while in females processing speed (β = 0.403, p = 0.003), executive function (β = 0.299, p = 0.020) and CR (β = -0.307, p = 0.012) were significantly associated with functioning., Conclusion: Our data indicate that predictors of functioning at 2-year follow-up in the FEP group differ according to sex. Therefore, treatment and preventative efforts may be adjusted taking sex into account. Males may benefit from functional remediation at early stages. Conversely, in females, early interventions centered on CR enhancement and cognitive rehabilitation may be recommended., Competing Interests: EV has received grants and served as consultant, advisor or CME speaker for the following entities (unrelated to the present work): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Sage, Sanofi-Aventis, and Takeda. JR-Q was on the speakers’ bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, Novartis, Shire, Takeda, Bial, Shionogui, Lundbeck, Almirall, Braingaze, Sincrolab, Medice and Rubió, Raffo in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Takeda, Shionogui, Bial, Medice and Eli- Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli-Lilly, Lundbeck, Janssen-Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió. MB has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Angelini, Casen Recordati, Janssen-Cilag, Menarini, Rovi and Takeda. NV has received financial support for CME activities and travel funds from the following entities (unrelated to the present work): Angelini, Janssen-Cilag, Lundbeck, Otsuka. CDLC received financial support to attend scientific meetings from Janssen, Almirall, Lilly, Lundbeck, Rovi, Esteve, Novartis, Astrazeneca, Pfizer and Casen Recordati. IB has received honoraria or travel support to attend conferences from Angelini, Janssen and Otsuka-Lundbeck; and grants from Instituto de Salud Carlos III, Spanish ministry of Health. LG-B has received honoraria for lecturing and/or travel grants for attending conferences from the Spanish Foundation of Psychiatry and Mental Health, Otsuka, Lundbeck, Janssen-Cilag, Servier, Angelini and Pfizer. NA has received CME-related financing from Janssen-Cilag, Lundbeck, Adamed, Pfizer and Boston Scientific, outside the submitted work. LI has received medical education support from Otsuka-Lundbeck, and training courses support from Otsuka-Lundbeck, Adamed and Janssen. RR-J has been a consultant for, spoken in activities of, or received grants from: Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/BMD-2422 AGES; S2017/BMD-3740), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Casen-Recordati, Angelini. JG-D was partly funded by a grant from Ministerio de Ciencia y Tecnologia – Republica de Colombia (Convocatoria 885/2020) and has been an advisor/speaker for, or received travel support from Janssen, Eurofarma, Servier, Sanofi, Lilly, and Pfizer. AI has received research support from or served as speaker or advisor for Janssen-Cilag, Lundbeck and Otsuka. MR-C is a Ramon y Cajal Research Fellow (RYC-2017-23144), Spanish Ministry of Science, Innovation and Universities and was supported by a NARSAD independent investigator grant (no. 24628) from the Brain and Behavior Research Foundation. MC has received grant support from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (PI18/00753, PI21/00701) and the Alicia Koplowitz Foundation. CMD-C has received grant support from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (PI17/00481, PI20/00721, JR19/0024) and honoraria from Exeltis and Angelini. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Serra-Navarro, Amoretti, Verdolini, Forte, Sánchez-Torres, Vieta, Clougher, Lobo, González-Pinto, Panadero, Roldán, Carvalho, de la Serna, Toll, Ramos-Quiroga, Torrent, Cuesta, Bernardo and PEPs Group.)