BACKGROUND: Debate continues as to whether surgical treatment with chondral-regeneration devices is superior to microfracture for focal articular cartilage defects in the knee. PURPOSE: To evaluate the superiority of scaffold-associated chondral-regeneration procedures over microfracture by assessing: (1) Patient-reported outcomes; (2) Intervention failure; (3) Histological quality of cartilage repair. STUDY DESIGN: A three-concept keyword search strategy was designed, in accordance with PRISMA guidelines: (i) knee (ii) microfracture (iii) scaffold. Four databases (Ovid Medline, Embase, CINAHL and Scopus) were searched for comparative clinical trials (Level I-III evidence). Critical appraisal used two Cochrane tools: the Risk of Bias tool (RoB2) for randomized control trials and the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I). Study heterogeneity permitted qualitative analysis with the exception of three patient-reported scores, for which a meta-analysis was performed. RESULTS: Twenty-one studies were identified (1699 patients, age range 18-66 years): ten randomized control trials and eleven non-randomized study interventions. Meta-analyses of the International Knee Documentation Committee (IKDC), Knee Injury And Osteoarthritis Outcome Score (KOOS) for pain and activities of daily living, and Lysholm score demonstrated statistically significant improvement in outcomes for scaffold procedures compared to microfracture at two years. No statistical difference was seen at five years. CONCLUSION: Despite the limitations of study heterogeneity, scaffold-associated procedures appear to be superior to MF in terms of patient-reported outcomes at two years though similar at five years. Future evaluation would benefit from studies using validated clinical scoring systems, reporting failure, adverse events and long-term clinical follow up to determine technique safety and superiority.