OBJECTIVES: Combination pharmacotherapy is often necessary to treat hypertension, but can negatively impact patient compliance. This analysis assesses the impact of combination therapy with valsartan and amlodipine, with or without hydrochlorthiazide (HCTZ), on medication possession ratios (MPR) in a previously antihypertensive naïve population. METHODS: A national database of insured hypertensive patients > age 18 previously antihypertensive naïve was evaluated for combination pharmacotherapy. Dual therapy with valsartan and amlodipine was initiated within the first 180 days of pharmacotherapy. Triple therapy with valsartan-amlodipine-HCTZ could occur in two manners during the first 365 days of pharmacotherapy: combination as three free drug components, or a proprietary fixed dose combination of valsartan and HCTZ with amlodipine. All three groups had at least two claims for the combination during the 365 days following initiation of the combination. RESULTS: Using hypertension ICD-9 codes (401.0, 401.1, 401.9, 402.1 & 402.9) 908 subjects met study criteria for combination pharmacotherapy: 224 on dual therapy, 63 on free triple therapy, and 615 on fixed dose triple therapy. MPR values decreased with the increase in tablets per regimen: dual therapy 0.779, fixed dose triple 0.734, free triple 0.694 (P=0.0149). A trend towards improved MPR with increasing age was noted between cohorts, and in the general population increased from 0.7 in ages 18-35 to 0.77 for subjects > 65 (P=0.0058) A trend towards improved MPR with increasing severity of cardiovascular disease was also noted. MPR values for subjects with the highest disease burden (>2 comorbid cardiovascular diseases) followed a similar pattern: dual 0.791, triple fixed 0.745, triple free 0.654 (P=0.067). CONCLUSION: Patient compliance improves with simplified pharmacotherapy approaches. Dual therapy provided the best MPR values, followed by triple drug therapy using two tablets (fixed dose valsartan HCTZ plus amlodipine). Other factors positively influencing compliance were advancing age and overall cardiac disease burden.