Background: Microfracture (MFx) is the most common procedure for treating chondral lesions in the knee; however, initial improvements decline after 2 years. Autologous matrix-induced chondrogenesis (AMIC) may overcome this shortcoming by combining MFx with collagen scaffolds. However, the outcomes of AMIC and MFx in the knee have not been compared. Purpose: To compare the clinical and radiological outcomes of AMIC and MFx over a minimum 2-year follow-up. Study Design: Systematic review; Level of evidence, 4. Methods: A systematic search of the MEDLINE, Embase, and Cochrane Library databases identified studies of patients who underwent AMIC or MFx and that reported validated clinical outcome measure and/or radiological evaluation findings at a follow-up of ≥2 years. There were 2 reviewers who performed study selection, a risk of bias assessment, and data extraction. Results: Overall, 29 studies were included in this systematic review. The mean improvement on the Lysholm score, Tegner activity scale, and visual analog scale for pain did not differ significantly between the 2 procedures. The mean improvement on the International Knee Documentation Committee (IKDC) subjective score was significantly greater in the AMIC (45.9 [95% CI, 36.2-55.5]) than in the MFx (27.2 [95% CI, 23.3-31.1]) group ( P < .001). In addition, the mean magnetic resonance observation of cartilage repair tissue score was significantly higher in the AMIC (69.3 [95% CI, 55.1-83.5]) versus MFx (41.0 [95% CI, 27.3-54.7]) group ( P = .005), and the mean adequate defect filling rate on magnetic resonance imaging scans was significantly better in the AMIC (77.3% [95% CI, 66.7%-87.9%]) versus MFx (47.9% [95% CI, 29.2%-66.6%]) group ( P = .008) (odds ratio, 1.58 [95% CI, 1.07-2.33]). Conclusion: No significant differences in clinical outcomes, except for the IKDC subjective score, were found between the AMIC and MFx groups. Greater improvement in IKDC subjective scores and magnetic resonance imaging findings were seen in patients treated with AMIC compared with MFx at a minimum 2-year follow-up.