Introduction: The objectives of continuing medical education (CME) programs include knowledge acquisition, skill development, clinical reasoning and decision making, and health care outcomes. We conducted a yearlong medical education research study in which knowledge acquisition in our CME programs was assessed. Method: A randomized separate-sample pretest/post-test design, a quasi-experimental technique, was used. Nine CME programs with a sufficient number of participants were identified a priori. Knowledge acquisition was compared between the control group and the intervention group for the nine individual programs and for the combined programs. Results: A total of 667 physicians, nurses, and other health professionals participated. Significant gain in knowledge was found for six programs: Perinatology, Pain Management, Fertility Care 2, Pediatrics, Colorectal Diseases, and Alzheimer's Disease (each p less than 0.001). Also, the intervention group differed from the control group when the nine programs were combined (p less than 0.001), with an effect size of 0.84. Discussion: The use of sound quasi-experimental research methodology (separate-sample pretest/post-test design), the inclusion of a representative sample of CME programs, and the analysis of nearly 700 subjects led us to have confidence in concluding that our CME participants acquired a meaningful amount of new knowledge. (Contains 1 table.)