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Background: The widening gap between innovations in the medical field and the dissemination of such information to doctors may affect the quality of care. Offline computer-based digital education (OCDE) may be a potential solution to overcoming the geographical, financial, and temporal obstacles faced by doctors. Objective: The objectives of this systematic review were to evaluate the effectiveness of OCDE compared with face-to-face learning, no intervention, or other types of digital learning for improving medical doctors’ knowledge, cognitive skills, and patient-related outcomes. Secondary objectives were to assess the cost-effectiveness (CE) of OCDE and any adverse effects. Methods: We searched major bibliographic databases from 1990 to August 2017 to identify relevant articles and followed the Cochrane methodology for systematic reviews of intervention. Results: Overall, 27 randomized controlled trials (RCTs), 1 cluster RCT (cRCT), and 1 quasi-RCT were included in this review. The total number of participants was 1690 in addition to the cRCT, which included 24 practices. Due to the heterogeneity of the participants, interventions, and outcomes, meta-analysis was not feasible, and the results were presented as narrative summary. Compared with face-to-face learning, the effect of OCDE on knowledge gain is uncertain (ratio of the means [RM] range 0.95-1.17; 8 studies, 495 participants; very low grade of evidence). From the same comparison, the effect of OCDE on cognitive skill gain is uncertain (RM range 0.1-0.9; 8 studies, 375 participants; very low grade of evidence). OCDE may have little or no effect on patients’ outcome compared with face-to-face education (2 studies, 62 participants; low grade of evidence). Compared with no intervention, OCDE may improve knowledge gain (RM range 1.36-0.98; 4 studies, 401 participants; low grade of evidence). From the same comparison, the effect of OCDE on cognitive skill gain is uncertain (RM range 1.1-1.15; 4 trials, 495 participants; very low grade of evidence). One cRCT, involving 24 practices, investigated patients’ outcome in this comparison and showed no difference between the 2 groups with low-grade evidence. Compared with text-based learning, the effect of OCDE on cognitive skills gain is uncertain (RM range 0.91-1.46; 3 trials with 4 interventions; 68 participants; very low-grade evidence). No study in this comparison investigated knowledge gain or patients’ outcomes. One study assessed the CE and showed that OCDE was cost-effective when compared with face-to-face learning if the cost is less than or equal to Can $200. No trial evaluated the adverse effect of OCDE. Conclusions: The effect of OCDE compared with other methods of education on medical doctors’ knowledge and cognitive skill gain is uncertain. OCDE may improve doctors’ knowledge compared with no intervention but its effect on doctors’ cognitive skills is uncertain. OCDE may have little or no effect in improving patients’ outcome. Published version