Purpose: A recent systematic review (2008) described the effectiveness of Internet-based learning (IBL) in health professions education. A comprehensive synthesis of research investigating how to improve IBL is needed. This systematic review sought to provide such a synthesis. METHOD: The authors searched MEDLINE, CINAHL, EMBASE, Web of Science, Scopus, ERIC, TimeLit, and the University of Toronto Research and Development Resource Base for articles published from 1990 through November 2008. They included all studies quantifying the effect of IBL compared with another Internet-based or computer-assisted instructional intervention on practicing and student physicians, nurses, pharmacists, dentists, and other health professionals. Reviewers working independently and in duplicate abstracted information, coded study quality, and grouped studies according to inductively identified themes. RESULTS: From 2,705 articles, the authors identified 51 eligible studies, including 30 randomized trials. The pooled effect size (ES) for learning outcomes in 15 studies investigating high versus low interactivity was 0.27 (95% confidence interval, 0.08-0.46; P = .006). Also associated with higher learning were practice exercises (ES 0.40 [0.08-0.71; P = .01]; 10 studies), feedback (ES 0.68 [0.01-1.35; P = .047]; 2 studies), and repetition of study material (ES 0.19 [0.09-0.30; P < .001]; 2 studies). The ES was 0.26 (-0.62 to 1.13; P = .57) for three studies examining online discussion. Inconsistency was large (I >89%) in most analyses. Meta-analyses for other themes generally yielded imprecise results. CONCLUSIONS: Interactivity, practice exercises, repetition, and feedback seem to be associated with improved learning outcomes, although inconsistency across studies tempers conclusions. Evidence for other instructional variations remains inconclusive. Copyright © by the Association of American Medical Colleges.