Background: The short-term outcomes of anterior cruciate ligament (ACL) reconstruction with bone–patellar tendon–bone or hamstring tendon (HT) graft are excellent with good clinical stability and patient-reported outcomes. Although some studies have reported the long-term outcomes of bone–patellar tendon–bone graft ACL reconstruction, few have reported the outcomes of HT graft ACL reconstruction. Purpose: To assess clinical and radiographic outcomes of HT graft ACL reconstruction with femoral cortical button fixation at a minimum 20-year follow-up. Study Design: Case series; Level of evidence, 4. Methods: A prospective study was performed in which all patients undergoing isolated transtibial primary ACL reconstruction between 1994 and 1996 with HT graft and femoral cortical button fixation were assessed clinically and radiographically. Follow-up was obtained in 48 of 94 patients (51%). Median (interquartile range) age at operation was 31 years (26-39 years); median follow-up was 21 years (20-22 years); 65% were male; and 48% had meniscal injury at surgery and underwent partial meniscectomy. Graft rupture, reoperation, and contralateral injury rates were assessed; clinical stability was measured using the KT-1000 arthrometer; patient-reported outcomes were assessed (International Knee Documentation Committee [IKDC], Lysholm, Forgotten Joint Score, Tegner activity, Knee injury and Osteoarthritis Outcome Score [KOOS], Anterior Cruciate Ligament Quality of Life [ACL-QOL], EuroQol 5-Dimension 5-Level [EQ-5D-5L]); and radiographic osteoarthritis (defined as Kellgren-Lawrence grade ≥2) was assessed for the ipsilateral and the contralateral knee. Results: Graft rupture occurred in 4 patients (8%), contralateral injury in 4 patients (8%), and reoperation in 15 patients (31%), which consisted mainly of meniscal tears or hardware removal. In patients with an intact graft, excellent patient-reported outcome measures (PROMs) were noted, with a median Lysholm of 90 (78-100), subjective IKDC of 86 (72-95), and KOOS–Sports of 86 (58-100). There was low awareness of the operated knee (Forgotten Joint Score, 81 [60-96]) and good quality of life (ACL-QOL, 85 [75-94]; EQ-5D-5L, 0.87 [0.83-1.00]). Median side-to-side difference, as measured with the KT-1000 arthrometer, was 1 mm (-1 to 3 mm). Radiographic osteoarthritis was evident in 49% of ipsilateral and 10% of contralateral knees and was associated with meniscectomy at index surgery and decreased PROMs at follow-up. Conclusion: Long-term outcomes of transtibial HT graft ACL reconstruction with femoral cortical button fixation are generally good with a low failure rate, low awareness of the operated knee, and good clinical stability. Radiographic osteoarthritis was evident in approximately half of the patients at 20-year follow-up and was associated with meniscectomy at index surgery and decreased PROMs at follow-up.