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BACKGROUND Black cisgender gay, bisexual and other sexual minority men (SMM) and transgender women (TW) continue to be heavily impacted by HIV. Further research is needed to better understand HIV prevention and care outcomes among Black SMM and TW, including the impact of substance use and sleep health, as well as whether neighborhood and network factors mediate and moderate these relationships. OBJECTIVE The current paper outlines the study methods being utilized in the recently launched follow-up study to the Neighborhoods and Networks (N2) study, which we refer to as N2 Part 2 (N2P2). METHODS Building on the N2 Cohort Study in Chicago from 2018 to 2022, N2P2 employs a prospective longitudinal cohort design and observational-implementation hybrid approach. With sustained high levels of community engagement, we aim to recruit a new sample of 600 Black SMM and TW participants residing in the Chicago metropolitan statistical area (MSA). Participants are asked to partake in three study visits across an 18-month study-period (one visit every 9 months). Four different forms of data are collected per wave: (1) an in-person survey, (2) biological specimen collection, (3) a daily remote ecological momentary assessment (EMA) for 14 days after each study visit, and (4) data from electronic health records (EHR). These forms of data collection continue to assess neighborhood and network factors and specifically explore substance use, sleep, immune function, obesity, and implementation of potential interventions that address relevant constructs (e.g., alcohol use, PrEP adherence). RESULTS The N2P2 study was funded in August 2021 by the National Institute of Drug Abuse (R01DA054553 and R21DA053156) and National Heart, Lung, and Brain Institute (R01HL160325). The study was launched in November 2022. Recruitment and enrollment for the first wave of data collection is still ongoing. CONCLUSIONS The N2P2 study is applying innovative methods to comprehensively explore the impacts of substance use and sleep health on HIV-related outcomes among an HIV status neutral cohort of Black SMM and TW in Chicago. The study is applying an observational-implementation hybrid design in order to help us achieve findings that support rapid translation, a critical priority among populations such as Black SMM and TW that experience long-standing inequities with regards to HIV and other health-related outcomes. N2P2 will directly build off of the findings that have resulted from the original N2 study among Black SMM and TW in Chicago. These findings include a better understanding of multi-level (e.g., individual, network, neighborhood) factors that contribute to HIV-related outcomes and viral suppression among Black SMM and TW.