BACKGROUND: Social media is increasingly used to deliver HIV interventions for key populations worldwide. However, little is known about the specific uses and effects of social media on human immunodeficiency virus (HIV) interventions. OBJECTIVE: This systematic review examines the effectiveness of social media interventions to promote HIV testing, linkage, adherence, and retention among key populations. METHODS: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and Cochrane guidelines for this review and registered it on the International Prospective Register of Systematic Reviews, PROSPERO. We systematically searched six databases and three conference websites using search terms related to HIV, social media, and key populations. We included studies where (1) the intervention was created or implemented on social media platforms, (2) study population included men who have sex with men (MSM), transgender individuals, people who inject drugs (PWID), and/or sex workers, and (3) outcomes included promoting HIV testing, linkage, adherence, and/or retention. Meta-analyses were conducted by Review Manager, version 5.3. Pooled relative risk (RR) and 95% confidence intervals were calculated by random-effects models. RESULTS: Among 981 manuscripts identified, 26 studies met the inclusion criteria. We found 18 studies from high-income countries, 8 in middle-income countries, and 0 in low-income countries. Eight were randomized controlled trials, and 18 were observational studies. All studies (n=26) included MSM; five studies also included transgender individuals. The focus of 21 studies was HIV testing, four on HIV testing and linkage to care, and one on antiretroviral therapy adherence. Social media interventions were used to do the following: build online interactive communities to encourage HIV testing/adherence (10 studies), provide HIV testing services (9 studies), disseminate HIV information (9 studies), and develop intervention materials (1 study). Of the studies providing HIV self-testing, 16% of participants requested HIV testing kits from social media platforms. Existing social media platforms such as Facebook (n=15) and the gay dating app Grindr (n=10) were used most frequently. Data from four studies show that HIV testing uptake increased after social media interventions (n=1283, RR 1.50, 95% CI 1.28-1.76). In the studies where social media interventions were participatory, HIV testing uptake was higher in the intervention arm than the comparison arm (n=1023, RR 1.64, 95% CI 1.19-2.26). CONCLUSIONS: Social media interventions are effective in promoting HIV testing among MSM in many settings. Social media interventions to improve HIV services beyond HIV testing in low- and middle-income countries and among other key populations need to be considered. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO): CRD42016048073; http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42016048073 (Archived by WebCite at http://www. webcitation.org/6usLCJK3v).