Office, home, and ambulatory blood pressure (BP) demonstrate variable associations with outcomes. The authors sought to compare office BP (OBP), home BP (HBP), and ambulatory BP (ABP) for measuring responses to hydrochlorothiazide (HCTZ), atenolol, and their combination. After completing washout, eligible patients were randomized to atenolol 50 mg or HCTZ 12.5 mg daily. Doses were doubled after 3 weeks and the alternate drug was added after 6 weeks if BP was >120/70 mm Hg (chosen to allow maximum opportunity to assess genetic associations with dual BP therapy in the parent study). OBP (in triplicate), HBP (twice daily for 5 days), and 24-hour ABP were measured at baseline, after monotherapy, and after combination therapy. BP responses were compared between OBP, HBP, and ABP for each monotherapy and combination therapy. In 418 patients, OBP overestimated BP response compared with HBP, with an average 4.6 mm Hg greater reduction in systolic BP (P<.0001) and 2.1 mm Hg greater reduction in diastolic BP (P<.0001) across all therapies. Results were similar for atenolol and HCTZ monotherapy. ABP response was more highly correlated with HBP response (r=0.58) than with OBP response (r=0.47; P=.04). In the context of a randomized clinical trial, the authors have identified significant differences in HBP, OBP, and ABP methods of measuring BP response to atenolol and HCTZ monotherapy.