Background-Indirect evidence shows that alerting users with clinical decision support systems seems to change behavior more than requiring users to actively initiate the system. However, randomized trials comparing these methods in a clinical setting are lacking. We studied the effect of both alerting and on-demand decision support with respect to screening and treatment of dyslipidemia based on the guidelines of the Dutch College of General Practitioners. Methods and Results-In a clustered randomized trial design, 38 Dutch general practices (77 physicians) and 87 886 of their patients (39 433 men 18 to 70 years of age and 48 453 women 18 to 75 years of age) who used the ELIAS electronic health record participated. Each practice was assigned to receive alerts, on-demand support, or no intervention. We measured the percentage of patients screened and treated after 12 months of follow-up. In the alerting group, 65% of the patients requiring screening were screened (relative risk versus control = 1.76; 95% confidence interval, 1.41 to 2.20) compared with 35% of patients in the on-demand group (relative risk versus control = 1.28; 95% confidence interval, 0.98 to 1.68) and 25% of patients in the control group. In the alerting group, 66% of patients requiring treatment were treated (relative risk versus control = 1.40; 95% confidence interval, 1.15 to 1.70) compared with 40% of patients (relative risk versus control = 1.19; 95% confidence interval, 0.94 to 1.50) in the on-demand group and 36% of patients in the control group. Conclusion-The alerting version of the clinical decision support systems significantly improved screening and treatment performance for dyslipidemia by general practitioners.