Background: Little is known about the prevalence of suicidal ideation among U.S. medical students or how it relates to burnout. Objective: To assess the frequency of suicidal ideation among medical students and explore its relationship with burnout. Design: Cross-sectional 2007 and longitudinal 2006 to 2007 cohort study. Setting: 7 medical schools in the United States. Participants: 4287 medical students at 7 medical schools, with students at 5 institutions studied longitudinally. Measurements: Prevalence of suicidal ideation in the past year and its relationship to burnout, demographic characteristics, and quality of life. Results: Burnout was reported by 49.6% (95% CI, 47.5% to 51.8%) of students, and 11.2% (CI, 9.9% to 12.6%) reported suicidal ideation within the past year. In a sensitivity analysis that assumed all nonresponders did not have suicidal ideation, the prevalence of suicidal ideation in the past 12 months would be 5.8%. In the longitudinal cohort, burnout (P < 0.001 for all domains), quality of life (P < 0.002 for each domain), and depressive symptoms (P < 0.001) at baseline predicted suicidal ideation over the following year. In multivariable analysis, burnout and low mental quality of life at baseline were independent predictors of suicidal ideation over the following year. Of the 370 students who met criteria for burnout in 2006, 99 (26.8%) recovered. Recovery from burnout was associated with markedly less suicidal ideation, which suggests that recovery from burnout decreased suicide risk. Limitation: Although response rates (52% for the cross-sectional study and 65% for the longitudinal cohort study) are typical of physician surveys, nonresponse by some students reduces the precision of the estimated frequency of suicidal ideation and burnout. Conclusion: Approximately 50% of students experience burnout and 10% experience suicidal ideation during medical school. Burnout seems to be associated with increased likelihood of subsequent suicidal ideation, whereas recovery from burnout is associated with less suicidal ideation. © 2008 American College of Physicians.