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Aims: Women with atrial fibrillation (AF) are under-represented in randomised controlled trials (RCTs) of direct oral anticoagulants (DOACs). This systematic review and meta-analysis of RCTs and observational studies examined sex-specific outcomes of DOACs in AF., Methods: PubMed, Embase, Web of Science and Cochrane Library were searched from January 2008 to November 2022. Sex-specific comparative outcomes of stroke/systemic embolism (SE), major bleeding, intracranial haemorrhage (ICH) and gastrointestinal bleeding (GIB) between oral anticoagulants were pooled using random effects models. P values for interaction were calculated to examine differences in results between sexes. RCTs and observational studies were meta-analysed separately., Results: 5 RCTs and 33 observational studies were included, totalling 1 085 931 women and 1 387 123 men. Meta-analyses showed that for both sexes, DOAC versus warfarin was generally associated with lower risk of stroke/SE, major bleeding and ICH; in DOAC-DOAC comparisons, rivaroxaban versus dabigatran had higher GIB risk. The only sex-specific difference observed was that when compared with warfarin, women had higher GIB risk with rivaroxaban (women: pooled risk ratio (pRR)=1.34, 95% CI=1.18 to 1.51; men: pRR=0.97, 95% CI=0.85 to 1.10; p value for interaction (p for interaction)<0.001) and possibly dabigatran (women: pRR=1.25, 95% CI=0.92 to 1.70; men: pRR=0.83, 95% CI=0.72 to 0.97; p-for-interaction=0.02). The sex difference in GIB remained for rivaroxaban when a Bonferroni-corrected significance level was used (α=0.003). No sex-specific GIB data for apixaban and edoxaban was available for the meta-analysis., Conclusions: For both sexes, DOACs generally demonstrated favourable effectiveness and safety over warfarin. However, observational data suggested that women may have higher GIB risk with rivaroxaban and possibly dabigatran than warfarin. Further studies are warranted to verify our findings and elucidate sex-specific GIB risk with apixaban and edoxaban, of which the data is currently lacking., Prospero Registration Number: CRD42022325027., Competing Interests: Competing interests: ZW’s current post is partly supported by the AIR@InnoHK administered by Innovation and Technology Commission. KKCM was supported by the CW Maplethorpe Fellowship and received research funding from the National Institute of Health Research, UK, European Commission Horizon 2020 framework and Hong Kong Research Grants Council and personal fee from IQVIA, outside the scope of the submitted work. GYHL is consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Anthos and Daiichi-Sankyo, no fees was received personally. ICKW has received research funding from the National Institute of Health Research, UK, European Commission Horizon 2020 framework, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, Amgen, Janssen, Novartis and GSK for medication safety research, outside the scope of the submitted work. He also received funding from Bristol-Myers Squibb, Pfizer and Bayer on DOACs research but it is not associated with the current study. His current post is partly funded by the AIR@InnoHK administered by Innovation and Technology Commission. WL reported research funding from the AIR@InnoHK administered by Innovation and Technology Commission, outside the scope of the submitted work. There are no other relationships or activities to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)