OBJECTIVES: To compare compliance/persistence, healthcare utilization, and costs associated with aliskiren+ARB vs. ARB+ACEI combination therapies among adult patients with hypertension. METHODS: Patients with hypertension (age≥18) initiated on combination therapy (≥15 days of overlap) with aliskiren+ARB or ARB+ACEI during July 2007-June 2008 were identified in the MarketScan Database. Study outcomes were measured during the 6-month study period, including medication possession ratio (MPR), treatment discontinuation rates, resource utilization, and changes in health care costs (from 6-month baseline to study period). Risk-adjusted differences in outcomes between aliskiren+ARB vs. ARB+ACEI patients and their 95% confidence intervals (CIs) were estimated using multivariate regression models, controlling for demographics, comorbidities, prescription drug use, and healthcare resource utilization during the baseline period. RESULTS: Comorbidity profiles were similar between patients on aliskiren+ARB (N=1,395) vs. ARB+ACEI (N=16,507), though baseline resource utilization and costs were different between the cohorts. Adjusting for baseline characteristics, aliskiren+ARB patients demonstrated significantly higher MPR (difference=15.2% [95% CI: 13.0%, 17.4%]) and lower discontinuation rate (odds ratio=0.43 [95% CI: 0.37, 0.51]) than ARB+ACEI patients. Aliskiren+ARB patients had fewer all-cause hospitalizations (adjusted incidence rate ratio [IRR]=0.73 [95% CI: 0.61, 0.86]) and fewer all-cause emergency room (ER) visits (adjusted IRR=0.72 [95% CI: 0.61, 0.85]) than ARB+ACEI patients; results for cardiovascular-related hospitalizations and ER visits were similar. Compared to ARB+ACEI patients, aliskiren+ARB patients had larger increases in prescription costs by $264 during the 6 months following therapy initiation (95% CI: $153, $375), but showed a trend in reducing total healthcare costs by -$583 (95% CI: -$2,409, $1,242) during the same 6-month period.  CONCLUSIONS: Patients with hypertension initiated on aliskiren+ARB had significantly better compliance/persistence and lower frequencies of hospitalizations and ER visits than those initiated on ARB+ACEI. Trends indicated greater reductions in total healthcare costs with aliskiren+ARB, despite increased prescription costs.