Osteochondral allograft transplantation (OCAT) has become a standard-of-care treatment option for patients with large symptomatic articular defects. Recent advances in allograft science and OCAT protocols have been reported to result in consistently robust outcomes after OCAT in the knee. However, only short-term comparisons have been reported, and analyses are lacking for treatment failure risk factors that account for confounding variables. Midterm functional graft survival rate would exceed 80% for all OCATs combined, with consideration of risk factors for lower survivorship including older patient age, higher body mass index (BMI), tibiofemoral bipolar OCAT, and nonadherence to prescribed postoperative rehabilitation protocols. Case series; Level of evidence, 4. Patients with outcome data available at ≥5 years after primary OCAT using high chondrocyte-viability (HCV) osteochondral allografts were analyzed according to 2 clinically relevant definitions: (1) initial treatment failure, defined by revision or arthroplasty surgery performed for the primary OCAT at any time point during the study period; and (2) functional graft failure, defined by documented conversion to arthroplasty after primary or revision OCAT at any time point during the study period. Analyses were used to assess outcomes for each definition, separately for age group, sex, obesity status, tobacco use, type of OCAT surgery, osteotomy status, concurrent ligament surgery status, and adherence to postoperative protocols. Kaplan-Meier analyses were used to assess differences in survival rates, and Cox proportional hazards models were used to assess risk factors and multivariable relationships with survival. Patient-reported outcome measures for pain, function, mobility, and satisfaction were also analyzed. Analysis included 137 primary knee OCATs performed in 134 patients with a mean follow-up of 66 months (59 female, 75 male; mean age, 37.8 years; mean BMI, 28.5). The midterm (5- to 8-year) functional graft survival rate for patients undergoing primary OCAT in the knee using HCV grafts was 82% for all cases combined, ranging from 69% for tibiofemoral bipolar HCV OCATs to 89% for patellofemoral bipolar, 94% for multisurface unipolar, and 97% for single-surface unipolar. Initial treatment failure rates (revision or arthroplasty after primary OCAT) and OCAT nonsurvival rates (arthroplasty after primary or revision OCAT) were greater for older patient age, concurrent ligament reconstruction, tibiofemoral bipolar OCAT, and nonadherence to the prescribed postoperative rehabilitation protocols. When adjusted for patients' age, BMI, and tobacco use status, different surgery types did not demonstrate an increased risk for failure, while concurrent ligament reconstruction and nonadherence did. Patients who experienced functional graft survival after primary OCAT reported significantly greater improvements in PROMIS Physical Function and Mobility (Patient-Reported Outcomes Measurement Information System), International Knee Documentation Committee questionnaire, and Single Assessment Numeric Evaluation scores such that they were significantly higher at final follow-up as compared with patients who required arthroplasty. Patient-reported improvements in pain, function, and mobility exceeded minimal clinically important differences for ≥5 years after primary OCAT. When asked if they were satisfied with primary OCAT surgery, 76.2% of patients were very satisfied or satisfied with their results, while 8.5% were neutral and 15.4% were unsatisfied or very unsatisfied. With use of HCV osteochondral allografts, midterm (5- to 8-year) functional graft survival rates for patients undergoing primary OCAT in the knee were notably higher than previously reported midterm rates for traditional OCATs. When adjusted for patient characteristics, risk factors for nonsurvival included concurrent ligament reconstruction for knee instability and nonadherence to the prescribed postoperative rehabilitation protocols. Patients who experienced functional graft survival for ≥5 years after primary OCAT reported statistically significant and clinically meaningful improvements in pain, function, and mobility.