OBJECTIVES: High pill burden has been associated with poor adherence to HAART and adverse clinical outcomes. This study evaluated the impact of HAART as a single-tablet regimen (STR) and multiple-tablet regimen (MTR) on outcomes in HIV patients within the Veteran’s Affairs (VA) system. METHODS: A retrospective, cohort study assessed patient VA dispensation data for HIV medications during the study enrollment period (7/1/2006 to 9/30/2011). Patients were assigned to the following cohorts: STR if they received a HAART regimen of a single tablet/day or MTR if they received a regimen of ≥2 tablets/day and no single tablet/day regimen during the enrollment period. Patients were followed from the index date (start of HAART regimen) until the earliest of treatment discontinuation, end of study period, or last date of healthcare-related activity (eg, VA benefits file or death). Hospitalization and adherence (medication possession ratio [MPR] ≥95%) were evaluated. Multivariate cohort differences in outcomes were controlled for using Cox-proportional hazard and logistic models; covariates were measured during a 6-month baseline period. RESULTS: In all, 15,602 patients (STR, n=6,191; MTR, n=9,411) met study criteria; average age of the study sample was 52 years. Both cohorts had similar CD4 counts (mean [SD]: 432.2 [282.8] vs 419.3 [280.9]; P=0.287) but significantly fewer patients receiving STR vs MTR had an undetectable viral load at baseline (42% vs 46%, P<0.001). During follow-up, significantly more STR patients were adherent compared to MTR patients (75% vs 55.7%, P<0.001). STR patients were also significantly less likely to experience hospitalization compared to MTR patients (26.8% vs 31.3%, P<0.001). After controlling for baseline covariates, STR patients had twice the odds of being adherent (OR: 1.98, P<0.001) and 31% lower hazard of experiencing hospitalization during follow-up (HR: 0.69, P<0.001). CONCLUSIONS: Treatment with STR compared to MTR improves adherence rates and decreases hospitalizations in patients with HIV/AIDS.