We conducted a systematic review and meta-analysis to assess the association between serosorting and HIV infection, sexually transmitted infections (STIs), and quality of life among men who have sex with men (MSM) and transgender people. Two reviewers independently screened abstracts and abstracted data. Meta-analyses were conducted using random effects models. Of 310 citations reviewed, 4 observational studies, all with MSM, met inclusion criteria. Compared to consistent condom use, serosorting was associated with increased risk of HIV (3 studies, odds ratio (OR): 1.80, 95% confidence interval (CI):1.21–2.70) and bacterial STIs (1 study, OR: 1.62, 95% CI: 1.44–1.83). Compared to no condom use, serosorting was associated with reduced risk of HIV (3 studies, OR: 0.46, 95% CI: 0.25–0.83) and bacterial STIs (1 study, OR: 0.81, 95% CI: 0.73–0.91). Among HIV-negative MSM, condom use appears to be more protective against HIV and STIs than serosorting and should be encouraged. However, serosorting may be better than no condom use as a harm reduction strategy.