Background Patient- and clinician-related factors may explain variability in blood pressure (BP) outcomes and the differences between real-world effectiveness and efficacy seen in randomized trials of antihypertensive agents. Objective To examine the effectiveness of 90 days of second-line valsartan treatment and identify patient- and physician-level determinants that impact BP outcomes. Methods A prospective, multicenter, multilevel pharmacoepidemiologic study was conducted in 3194 hypertensive patients (systolic BP [SBP] ≥140 mm Hg, diastolic BP [DBP] ≥90 mm Hg; for diabetic patients, ≥130 and ≥80 mm Hg, respectively) treated by 504 general practitioners (GPs). Statistical analysis included heuristic data mining, and hierarchical linear and logistic modeling. Results With valsartan treatment, mean ± SD SBP decreased from 154.4 ± 15.5 mm Hg to 139.0 ± 12.0 mm Hg and mean DBP decreased from 91.3 ± 9.2 mm Hg to 82.6 ± 7.4 mm Hg. SBP control rates increased from 9.0% to 38.6%, DBP from 25.5% to 65.5%, and combined SBP/DBP from 7.3% to 34.4%. A highly vulnerable cohort (n = 1063;35.4%) of patients was identified. Twenty-four percent of variability in SBP and 25% of variability in DBP at 90 days were attributable to physician-related variables: guideline-compliant BP management, hypertension, practice patterns, hypertensive patient volume, and years in practice. The remaining 76% and 75% of variability in SBP and DBP, respectively, were due to patient factors, notably diabetes and related complications, vulnerability to uncontrolled BP, nonadherence, cardiovascular risk, and age. Simitar factors increased the odds of treatment nonresponse, with diabetes being the single largest determinant of uncontrolled SBP (OR 8.99), DBP (OR 20.35), and combined SBP/DBP (OR = 18.64). Conclusions Valsartan is effective and well tolerated in a broad range of patients in whom first-line antihypertensive treatment failed or was not tolerated. Mitigating the impact of BP-elevating variables and optimizing the effect of BP-lowering factors provides therapeutic benefits incremental to valsartan's pharmacologic effect. Improving outcomes in hypertensive patients involves 3 steps: (1) identifying, intuitively rather than formally, patients less likely to achieve BP control; (2) targeting modifiable or manageable patient- and physician-level determinants with BP-elevating or BP-lowering effects; and (3) managing variables that increase the odds and optimizing those that lower the odds of uncontrolled BP.