The anterior cruciate ligament (ACL) prevents the anterior translocation and medial rotation of the tibia against the femur. It is typically composed of dense regular connective tissue (DRCT), small amount of loose connective tissue, little vasculature, and few nerve endings. The objective of the current study was to evaluate the details of histological changes in ACLs of patients with clinically diagnosed osteoarthritis (OA). The ACLs of six patients undergoing total knee replacement because of OA (OA group) were compared with 16 normal ACLs from cadavers (control). The ACLs were analyzed for tissue composition and number of blood vessels across the full length and thickness of the ligament. Percentages for areas of DRCT, fibrocartilage, degenerative tissue, and vasculature were calculated. Tissue composition and relative number of blood vessels were compared between groups. The proportion of DRCT to non-DRCT was significantly smaller in the OA group than the control group (p < .001); non-DRCT included degenerative connective tissue and fibrocartilage. The number of blood vessels to area was greater in the OA group than the control group (p = .002). Six of control (37.5%) and five of OA ACLs (83%) showed areas of calcification. These results indicate that inflammatory processes contributing to OA in the knee cause changes in the composition of the ACL that lead to destruction of collagen bundles, increased vascularization, calcification, and formation of fibrocartilage-like tissue inside the ligament. These changes make ligament-retaining total knee arthroplasty a less beneficial option for knee repair.