Background: Despite the increasing international popularity of CrossFit, there is a paucity of scientific evidence on the risk of CrossFit-related musculoskeletal injuries (CRMIs). Purpose: To investigate the incidence (cumulative incidence proportion [IP] and incidence density [ID]) of CRMIs and the association of CRMIs with personal and training characteristics. Study Design: Descriptive epidemiology study. Methods: A prospective, 12-week descriptive epidemiology cohort study was conducted in a convenience sample of CrossFit facilities in a single Brazilian city. Printed baseline questionnaires were distributed to 13 CrossFit boxes. All participants who filled out the questionnaire and consented to participate in the study were invited to respond to an online follow-up questionnaire every 2 weeks to collect data on CrossFit training characteristics and CRMIs. A CRMI was defined as any self-reported musculoskeletal injury or pain that prevented an athlete from exercising for at least 1 day. The IP was defined as the number of new cases divided by the entire population at risk, while the ID was defined as new events divided by the total person-time exposure in hours. Logistic mixed models were developed to investigate the association of CRMIs with personal and training characteristics. Results: A total of 515 CrossFit participants filled out the baseline questionnaire and provided informed consent, and 406 (78.8%) completed at least 1 follow-up measure. There were 133 participants who reported at least 1 CRMI during the study, and a total of 247 unique and new CRMIs were reported over a total estimated person-time exposure to CrossFit of 13,041 hours. The IP was 32.8% (95% CI, 28.4%-37.5%). The ID was 18.9 (95% CI, 16.6-21.3) per 1000 hours of CrossFit exposure. The shoulders (19.0%; n = 47) and lumbar spine (15.0%; n = 37) were most affected. Muscle injuries (45.3%; n = 112) and joint pain (24.7%; n = 61) were the most common CRMI types reported. Switching between prescribed and scaled down training loads (odds ratio [OR], 3.5 [95% CI, 1.7-7.3]) and previous injuries (OR, 3.2 [95% CI, 1.4-7.7]) were risk factors for a CRMI, while CrossFit experience was identified as a protective factor (OR, 0.7 [95% CI, 0.5-1.0]). Conclusion: In this 12-week prospective study, the ID was 18.9 CRMIs per 1000 hours of exposure; switching between training loads and previous injuries was associated with 3.5- and 3.2-fold higher odds, respectively, of sustaining CRMIs.