We examined baseline data from the Systolic Blood Pressure Intervention Trial (SPRINT) to investigate whether medication adherence, measured by the 8-item Morisky Medication Adherence Scale (MMAS-8), was associated with systolic blood pressure (SBP) and whether MMAS-8 score and number of antihypertensive medications interacted in influencing SBP. A total of 8435 SPRINT participants were included: 21.2% had low adherence (MMAS-8: <6); 40.0% had medium adherence (6 to <8); and 38.8% had high adherence (8). SBP was <140 mm Hg in 54.6%; 140-160 mm Hg in 36.6%; and >160 mm Hg in 8.8%. In multivariable regression, medium vs. low adherence weakly associated with lower SBP (odds ratio: 1.17; confidence interval: 1.04, 1.31). SPRINT eligibility criteria should be considered when interpreting results. Efforts to understand and enhance adherence are crucial to improve population health, and using self-report instruments might be considered for predicting treatment adherence and response in future efficacy trials and for identifying patients for adherence support in clinical practice.