OBJECTIVE To explore the influence of critical thinking, self-regulated learning and system usability on the acceptance of e-learning on patient safety. METHODS A cross-sectional study was conducted, using a 32-question online survey. One hundred ninety-three (n=193 medical students participated in the study and were asked to rate levels of reflective thinking, self-regulated learning and attitudes towards patient safety using scales from the Questionnaire for Reflective Thinking, the Attitudes to Patient Safety Questionnaire and the System Usability Scale. Differences between reflection levels were calculated using paired t-tests, associations between critical thinking and self-regulated learning were calculated using linear correlations. We performed linear multiple regression analysis to identify predictors for student acceptance of the e-learning. RESULTS Students (n=193) engaged in intermediate levels of reflection (5-point Likert, M=3.62, SD=0.73) and significantly (t(143)=15.15, p<0.001, d=1.57) lower levels (M=2.35, SD=0.87) of critical reflection. Most students showed high (≥ 4; 44.1%) or intermediate (<4 level > 2; 29.4 %) levels of self-regulated learning. A regression model indicated that 5 predictors (Reflection, critical reflection, self-regulated learning, relevance, usability) explained 65.3% of the variance (R²=0.653, F(5, 96)=39.02, p<0.01) of perceived total quality. CONCLUSIONS This study shows that reflection and learning skills are important factors for e-learning acceptance, but perceived relevance and system usability play a more important role.  From a didactic perspective, it is indispensable to provide the students with sufficient examples and links to professional practice to enhance the perception of relevance and to improve system usability permanently.