The anterior cruciate ligament (ACL) of the knee is an intra-articular ligament that fails to heal after primary repair. The medial collateral ligament (MCL) of the knee is an extra-articular ligament that heals uneventfully in the majority of cases. Why these two ligaments have such different responses to injury remains unclear. In this article, we address two hypotheses: first, that the histologic response to injury is different in intra-articular and extra-articular ligaments, and second, that the response of the intra-articular ligaments can be altered by placing a collagen-platelet-rich plasma (collagen-PRP) hydrogel in the wound site. Wounds were created in extra-articular ligaments (MCL and/or patellar ligament) and an intra-articular ligament (ACL) in canine knees, and the histologic response to injury evaluated at 3 days (n = 3), 7 days (n = 4), 3 weeks (n = 5), and 6 weeks (n = 5). In the 3-week (n = 5) and 6-week (n = 5) animals, bilateral central wounds were made in the ACLs and the wounds in one knee of each animal treated with a collagen-PRP hydrogel while the contralateral side was untreated. Extra-articular ligament wounds had greater filling of the wound site and increased presence in the wound site of fibrinogen, fibronectin, PDGF-A, TGF-beta1, FGF-2, and von Willebrand's factor when compared to intra-articular ligament wounds. Treatment of the intra-articular wound with a collagen-PRP hydrogel resulted in increased filling of the wound site with repair tissue that had similar profiles of growth factor and protein expression to the extra-articular ligament wounds. The use of a collagen-PRP scaffold can ameliorate histologic differences noted between healing extra-articular ligamentous wounds and nonhealing intra-articular ligamentous wounds. This study supports the hypothesis that premature scaffold failure may play a key role in the normally expected failure of the ACL to heal after injury.