OBJECTIVES: Adherence to ART is a key success factor for achieving optimal clinical outcomes in HIV disease. The objective was to assess differences in compliance rates and health care resource utilization between patients receiving a once daily single tablet regimen (STR) vs. a multiple tablets per day regimen (MTR). METHODS: This retrospective study included patients covered by the Quebec provincial drug reimbursement program (RAMQ) who have received at least one script for an ART from January 1st, 2006 to June 30th, 2012. For each patient, the index date was defined as the date of the first script for an ART and compliance rates were estimated over a 1-year period. Patients were considered compliant if their medication possession ratio (effective treatment duration over expected treatment duration) was equal or greater to 90%. Medical costs (hospitalizations and ER, outpatient clinic, ICU and physician’s visits) were compared between the STR group vs. the MTR group. Regression analyses were performed to assess the relationship between compliance, hospitalization rates and medical costs with the ART regimen, adjusting for age, gender, comorbidities scores, mental disorders diagnosis and drug and alcohol abuses.  RESULTS: The study included 4,996 HIV patients (mean age: 42.4 years, 74.8% males). A higher proportion of patients were compliant (88.4% vs. 75.8%) in the STR group compared to the MTR group (p<0.001). Patients receiving a MTR were 2.0-fold more likely to be non-compliant than patients receiving a STR (p<0.001). Moreover, hospitalization rates (25.8% vs. 15.9%, p<0.001) and medical costs (CAD$2,785 vs. CAD$1,909, p=0.008) were higher for patients receiving a MTR than a STR. Linear regression analyses also showed a positive relationship between MTR (vs. STR) and hospitalization rates (β=0.081,p=0.001) and medical costs (β=0.151,p<0.001).  CONCLUSIONS: Patients receiving a STR are more compliant than patients on a MTR and have lower hospitalization rates and medical costs.