Availability of a single source review of once-daily fixeddose single tablet regimen (STR) and multiple tablet fixed-dose regimen (MTR) would optimally inform healthcare providers and policy makers involved in the management of population with human immunodeficiency virus (HIV). We conducted a meta-Analysis of published literature to compare patient adherence, clinical, and cost outcomes of STR to MTR. Published literature in English between 2005 and 2014 was searched using Embase, PubMed (Medline in-process), and ClinicalTrials.Gov databases. Two-level screening was undertaken by 2 independent researchers to finalize articles for evidence synthesis. Adherence, efficacy, safety, tolerability, healthcare resource use (HRU), and costs were assessed comparing STR to MTR. A random-effects meta-Analysis was performed and heterogeneity examined using meta-regression. Thirty-five articles were identified for qualitative evidence synthesis, of which 9 had quantifiable data for meta-Analysis (4 randomized controlled trials and 5 observational studies). Patients on STR were significantly more adherent when compared to patients on MTR of any frequency (odds ratio [OR]: 2.37 [95% CI: 1.68, 3.35], P<0.001; 4 studies), twice-daily MTR (OR: 2.53 [95% CI: 1.13, 5.66], P0.02; 2 studies), and once-daily MTR (OR: 1.81 [95% CI: 1.15, 2.84], P0.01; 2 studies). The relative risk (RR) for viral load suppression at 48 weeks was higher (RR: 1.09 [95% CI: 1.04, 1.15], P.0003; 3 studies) while RR of grade 3 to 4 laboratory abnormalities was lower among patients on STR (RR: 0.68 [95% CI: 0.49, 0.94], P0.02; 2 studies). Changes in CD4 count at 48 weeks, any severe adverse events (SAEs), grade 3 to 4 AEs, mortality, and tolerability were found comparable between STR and MTR. Several studies reported significant reduction in HRU and costs among STR group versus MTR. Study depicted comparable tolerability, safety (All-SAE and Grade 34 AE), and mortality and fewer Grade 3 to 4 lab abnormalities and better viral load suppression and adherence among patients on FDCcontaining STR versus MTR; literature depicted favorable HRU and costs for STRs. These findings may help decision makers especially in resourcepoor settings to plan for optimal HIV disease management when the choice of both STRs and MTRs are available.