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The authors studied predictors of methylphenidate-induced increases in blood pressure (BP). In this secondary analysis of a randomized, double-blind, placebo-controlled smoking cessation trial, nonhypertensive adult smokers with attention deficit hyperactivity disorder randomized to osmotic-release oral system methylphenidate (OROS-MPH) (n=115) were matched one-to-one on baseline systolic BP (SBP) (±5 mm Hg) with participants randomized to placebo (n=115) and followed for 10 weeks. In adjusted mixed linear models of SBP and diastolic BP (DBP), baseline normal SBP (P<.0001) and DBP (P<.0001) were associated with significant OROS-MPH–induced increases compared with placebo, whereas significant increases were not observed in participants with baseline prehypertensive SBP (P=.27) and DBP (P=.79). Participants randomized to OROS-MPH with baseline normal BP had increased odds of developing either systolic (odds ratio [OR], 3.32; 95% confidence interval [CI], 1.41–8.37; P=.006) or diastolic prehypertension (OR, 4.32; 95% CI, 1.56–14.0; P=.004) compared with placebo using simple logistic regression. The authors demonstrated an augmented OROS-MPH–induced BP elevation and risk of prehypertension in adults with baseline normal BP. Significantly increased BP was not observed in adults with baseline prehypertension. J Clin Hypertens (Greenwich). 2012; 00:00–00. ©2012 Wiley Periodicals, Inc.