Focal cartilage lesions (FCLs) are frequently found during knee arthroscopies and may impair quality of life (QoL) significantly. Several treatment options with good short-term results are available, but the natural history without any treatment is largely unknown. The aim of this study was to evaluate patient-reported outcome measures (PROMs), the need for subsequent cartilage surgery, and the risk of treatment failure 20 years after diagnosis of an FCL in the knee. Patients undergoing any knee arthroscopy for an FCL between 1999 and 2012 in 6 major Norwegian hospitals were identified. Inclusion criteria were an arthroscopically classified FCL in the knee, patient age of ≥18 years at surgery, and any preoperative PROM. Exclusion criteria were lesions representing knee osteoarthritis or "kissing lesions" at surgery. Demographic data, later knee surgery, and PROMs were collected by questionnaire. Regression models were used to adjust for and evaluate the factors impacting the long-term PROMs and risk factors for treatment failure (defined as knee arthroplasty, osteotomy, or a Knee injury and Osteoarthritis Outcome Score-Quality of Life [KOOS QoL] subscore of <50). Of the 553 eligible patients, 322 evaluated patients (328 knees) were included and analyzed. The mean follow-up was 19.1 years, and the mean age at index FCL surgery was 36.8 years (95% confidence interval [CI], 35.6 to 38.0 years). The patients without knee arthroplasty or osteotomy had significantly better mean PROMs (pain, Lysholm, and KOOS) at the time of final follow-up than preoperatively. At the time of follow-up, 17.7% of the knees had undergone subsequent cartilage surgery. Nearly 50% of the patients had treatment failure, and the main risk factors were a body mass index of ≥25 kg/m2 (odds ratio [OR] for overweight patients, 2.0 [95% CI, 1.1 to 3.6]), >1 FCL (OR, 1.9 [CI, 1.1 to 3.3]), a full-thickness lesion (OR, 2.5 [95% CI, 1.3 to 5.0]), and a lower level of education (OR, 1.8 [95% Cl, 1.1 to 2.8]). Autologous chondrocyte implantation (ACI) was associated with significantly higher KOOS QoL, by 17.5 (95% CI, 3.2 to 31.7) points, and a lower risk of treatment failure compared with no cartilage treatment, microfracture, or mosaicplasty. After a mean follow-up of 19 years, patients with an FCL who did not require a subsequent knee arthroplasty had significantly higher PROM scores than preoperatively. Nonsurgical treatment of FCLs had results equal to those of the surgical FCL treatments except for ACI, which was associated with a better KOOS and lower risk of treatment failure. Full-thickness lesions, >1 FCL, a lower level of education, and a greater BMI were the main risk factors associated with poorer results. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.