PURPOSE: To investigate the combinations of variables that comprise the biopsychosocial model domains to identify clinical profiles of risk and protection of second anterior cruciate ligament injury. METHODS: One hundred and forty-five patients for return-to-sport testing after anterior cruciate ligament (ACL) reconstruction (ACLR) were contacted, and 97 were deemed eligible. All were evaluated between 6 and 24 months and followed up for 2 years. Participants answered the International Knee Documentation Committee (IKDC) and Anterior Cruciate Ligament-Return to Sport after Injury Scale (ACL-RSI), performed the postural stability assessment using the Biodex Balance System, and assessed muscle strength at 60° and 300°/s on the isokinetic dynamometer. Personal factors (age, gender, body mass index), body structures (graft type and concomitant injuries), and environmental factors (time between surgery and evaluation) were also collected. The participants were asked about the occurrence of a second ACL injury and return to sport after 2 years of follow-up. Classification and regression tree (CART) analysis was used to determine predictors of a second ACL injury. The receiver operating characteristic (ROC) curve was performed to verify the accuracy of the CART analysis, in addition to the sensitivity, specificity, and relative risk (RR) of the model. RESULTS: Of the initial 97 participants, 88 (89.8%) responded to follow-up and 14 (15.9%) had a second ACL injury (11 graft ruptures and three contralateral ACL). CART analysis identified the following variables as predictors of second ACL injury: return to sport, hamstring strength symmetry at 300°/s, ACL-RSI score, hamstrings/quadriceps ratio at 60°/s, and body mass index (BMI). CART correctly identified 9 (64.3%) of the 14 participants who were reinjured and 71 (95.9%) of the 74 participants who were not. The total correct classification was 90.9%. The area under the ROC curve was 0.88 (95% CI 0.72-0.99; p < 0.001), and the model showed a sensitivity of 75% (95% CI 42.8-94.5), specificity of 93.4% (95% CI 85.3-97.8), and RR of 15.9 (95% CI 4.9-51.4; p < 0.0001). CONCLUSION: The combination of hamstring strength symmetry, hamstring/quadriceps ratio (body functions); return to sport (activity and participation); psychological readiness; and BMI (personal factors) could identify three clinical risk profiles for a second ACL injury with good accuracy. LEVEL OF EVIDENCE: IV.