The increasing use of Internet-based learning in health professions education may be informed by a timely, comprehensive synthesis of evidence of effectiveness. To summarize the effect of Internet-based instruction for health professions learners compared with no intervention and with non-Internet interventions. Systematic search of MEDLINE, Scopus, CINAHL, EMBASE, ERIC, TimeLit, Web of Science, Dissertation Abstracts, and the University of Toronto Research and Development Resource Base from 1990 through 2007. Studies in any language quantifying the association of Internet-based instruction and educational outcomes for practicing and student physicians, nurses, pharmacists, dentists, and other health care professionals compared with a no-intervention or non-Internet control group or a preintervention assessment. Two reviewers independently evaluated study quality and abstracted information including characteristics of learners, learning setting, and intervention (including level of interactivity, practice exercises, online discussion, and duration). There were 201 eligible studies. Heterogeneity in results across studies was large (I(2) > or = 79%) in all analyses. Effect sizes were pooled using a random effects model. The pooled effect size in comparison to no intervention favored Internet-based interventions and was 1.00 (95% confidence interval [CI], 0.90-1.10; P < .001; n = 126 studies) for knowledge outcomes, 0.85 (95% CI, 0.49-1.20; P < .001; n = 16) for skills, and 0.82 (95% CI, 0.63-1.02; P < .001; n = 32) for learner behaviors and patient effects. Compared with non-Internet formats, the pooled effect sizes (positive numbers favoring Internet) were 0.10 (95% CI, -0.12 to 0.32; P = .37; n = 43) for satisfaction, 0.12 (95% CI, 0.003 to 0.24; P = .045; n = 63) for knowledge, 0.09 (95% CI, -0.26 to 0.44; P = .61; n = 12) for skills, and 0.51 (95% CI, -0.24 to 1.25; P = .18; n = 6) for behaviors or patient effects. No important treatment-subgroup interactions were identified. Internet-based learning is associated with large positive effects compared with no intervention. In contrast, effects compared with non-Internet instructional methods are heterogeneous and generally small, suggesting effectiveness similar to traditional methods. Future research should directly compare different Internet-based interventions.