Background: Decisions about hypertension management are substantially influenced by blood pressure (BP) levels measured before and soon after starting BP lowering drugs. We aimed to assess the utility of short-term BP changes in individuals in terms of long-term treatment response. Methods: Post hoc analyses of 2 randomized trials with 4-to-6 weeks active run-in for all participants, followed by randomization to active BP lowering treatment (combination perindopril±indapamide) or placebo. We categorized individuals by degree of systolic BP (SBP) change during active run-in treatment and assessed associations with subsequent postrandomization placebo-corrected BP reduction, cardiovascular events, and tolerability. We included individuals with baseline BP ≥140/90 mm Hg from the PROGRESS trial (Perindopril Protection Against Recurrent Stroke Study; 4275 individuals with cerebrovascular disease) and ADVANCE trial (The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation; 6610 individuals with diabetes). Results: During the active run-in period, the proportion of participants with initial SBP changes in 4 categories (SBP increase, 0–9.9 mm Hg decrease, 10–19.9 mm Hg decrease, and ≥20 mm Hg decrease) were 17%, 27%, 28%, and 28% in PROGRESS and 21%, 22%, 24%, and 33% in ADVANCE. Randomization to active therapy achieved similar placebo-corrected long-term BP reductions across the 4 initial SBP change groups in both trials ( P -values for heterogeneity >0.1). There was no significant difference in achieving BP <140/90 mm Hg at follow-up, major cardiovascular events, nor treatment tolerability according to the SBP change during active run-in period (all P -values >0.1). Conclusions: An individual’s apparent BP change immediately after commencing therapy has limited clinical utility. Therefore, more emphasis should be given to use of evidence-based regimens and measures over the long-term to ensure sustained BP control. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00145925.