Context: The increasing use of Internet-based learning in health professions education may be informed by a timely, comprehensive synthesis of evidence of effectiveness. Objectives: To summarize the effect of Internet-based instruction for health professions learners compared with no intervention and with non-Internet interventions. Data Sources: 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. Study Selection: 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. Data Extraction: 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). Data Synthesis: There were 201 eligible studies. Heterogeneity in results across studies was large (I2≥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. Conclusions: 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. ©2008 American Medical Association. All rights reserved.