Financial incentives can improve medication adherence and cardiovascular disease risk, but the optimal design to promote sustained adherence after incentives are discontinued is unknown. To determine whether 6-month interventions involving different financial incentives to encourage statin adherence reduce low-density lipoprotein cholesterol (LDL-C) levels from baseline to 12 months. This 4-group, randomized clinical trial was conducted from August 2013 to July 2018 among several large US insurer or employer populations and the University of Pennsylvania Health System. The study population included adults with elevated risk of cardiovascular disease, suboptimal LDL-C control, and evidence of imperfect adherence to statin medication. Data analysis was performed from July 2017 to June 2019. The interventions lasted 6 months during which all participants received daily medication reminders and an electronic pill bottle. Statin adherence was measured by opening the bottle. For participants randomized to the 3 intervention groups, adherence was rewarded with financial incentives. The sweepstakes group involved incentives for daily adherence. In the deadline sweepstakes group, incentives were reduced if participants were adherent only after a reminder. The sweepstakes plus deposit contract group split incentives between daily adherence and a monthly deposit reduced for each day of nonadherence. The primary outcome was change in LDL-C level from baseline to 12 months. Among 805 participants randomized (199 in the simple daily sweepstakes group, 204 in the deadline sweepstakes group, 201 in the sweepstakes plus deposit contract group, and 201 in the control group), the mean (SD) age was 58.5 (10.3) years; 519 participants (64.5%) were women, 514 (63.9%) had diabetes, and 273 (33.9%) had cardiovascular disease. The mean (SD) baseline LDL-C level was 143.2 (42.5) mg/dL. Measured adherence at 6 months (defined as the proportion of 180 days with electronic pill bottle opening) in the control group (0.69; 95% CI, 0.66-0.72) was lower than that in the simple sweepstakes group (0.84; 95% CI, 0.81-0.87), the deadline sweepstakes group (0.86; 95% CI, 0.83-0.89), and the sweepstakes plus deposit contract group (0.87; 95% CI, 0.84-0.90) (P < .001 for each incentive group vs control). LDL-C levels were measured for 636 participants at 12 months. Mean LDL-C level reductions from baseline to 12 months were 33.6 mg/dL (95% CI, 28.4-38.8 mg/dL) in the control group, 32.4 mg/dL (95% CI, 27.3-37.6 mg/dL) in the sweepstakes group, 33.2 mg/dL (95% CI, 28.1-38.3 mg/dL) in the deadline sweepstakes group, and 36.5 mg/dL (95% CI, 31.3-41.7 mg/dL) in the sweepstakes plus deposit contract group (adjusted P > .99 for each incentive group vs control). Compared with the control group, different financial incentives improved measured statin adherence but not LDL-C levels. This result points to the importance of directly measuring health outcomes, rather than simply adherence, in trials aimed at improving health behaviors. ClinicalTrials.gov Identifier: NCT01798784.