Background: Injury to the ipsilateral graft used for reconstruction of the anterior cruciate ligament (ACL) or a new injury to the contralateral ACL is a devastating outcome following successful ACL reconstruction, rehabilitation, and return to sport. Little evidence exists regarding the intermediate to long-term risk of these events. Methods: The present study is a systematic review of Level-I and II prospective studies that evaluated the rate of rupture of the ACL graft and the ACL in the contralateral knee following a primary ACL reconstruction with use of a mini-open or arthroscopic bone-tendon-bone or hamstring autograft after a minimum duration of follow-up of five years. Results: Six studies met the inclusion and exclusion criteria. The ipsilateral ACL graft rupture rate ranged from 1.8% to 10.4%, with a pooled percentage of 5.8%. The contralateral injury rate ranged from 8.2% to 16.0%, with a pooled percentage of 11.8%. Conclusions: This systematic review demonstrates that the risk of ACL tear in the contralateral knee (11.8%) is double the risk of ACL graft rupture in the ipsilateral knee (5.8%). Additional studies must be performed to determine predictors for these injuries and to improve our ability to avoid this devastating outcome. Level of Evidence: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.