BACKGROUND: The injury profile of each playing position in handball is a key factor in being able to improve the injury risk management process. Therefore, the aim of this study was to longitudinally analyze the differences in professional handball players' injury profile according to their playing position (ie, goalkeeper, back, wing, and line). HYPOTHESIS: Injury incidence and burden would be higher in back players compared with the other playing positions, while ligament and knee would be the most common injury type and location. STUDY DESIGN: Prospective cohort design. LEVEL OF EVIDENCE: Level 4. METHODS: Sixty-eight male handball players belonging to the same professional team participated in this study over 4 consecutive seasons. Injury incidence and injury burden were recorded as well as the severity, type, and location following the International Olympic Committee consensus statement. RESULTS: Although nonsignificant differences in injury incidence were found according to playing position (rate ratios [RRs] from 0.43 to 2.47; > 0.05), back players reported the highest burden (60.65 absence days/1000 h; RR from 0.12 to 7.75; < 0.05), with wing players showing a greater burden (54.29 absence days/1000 h; RR from 0.09 to 4.91; < 0.05) in comparison with goalkeepers (12.19 absence days/1000 h) and line players (13.10 absence days/1000 h). Muscle/tendon injuries and sprains presented higher incidence and burden than other type of injuries, and a greater incidence and burden was reported for knee injuries in all playing positions. CONCLUSION: The highest injury incidence and injury burden is in back players in professional handball. CLINICAL RELEVANCE: This study provides comprehensive information on the injury profile of professional handball players, which can be useful for strength and conditioning coaches when developing specific injury risk management programs.