Background: Arthroscopic microfracture for osteochondral lesion of the talus (OLT) has shown good functional outcomes in the short and long term. Purpose: To investigate 5-year radiographic and clinical outcomes after arthroscopic microfracture in treatment of OLT and the effectiveness of adjunct therapies including platelet-rich plasma (PRP) and hyaluronic acid (HA). Study Design: Cohort study; Level of evidence, 2. Methods: We prospectively enrolled 432 patients who underwent arthroscopic microfracture for OLT from May 1, 2011, to May 31, 2015. Magnetic resonance imaging (MRI) and weightbearing radiographs were performed annually after the initial surgery. The MOCART (magnetic resonance observation of cartilage repair tissue) score was used to evaluate the structure of the repaired cartilage on MRI, and patient-reported outcomes (American Orthopaedic Foot and Ankle Society ankle-hindfoot scale [AOFAS] and the Foot and Ankle Outcome Score) were collected annually. The primary outcome measure was 5-year AOFAS score. We recorded baseline characteristics including age, body mass index (BMI), and lesion size, and other potentially related factors including number of PRP/HA injection and change in BMI from baseline. Results: Included were 355 patients, all with minimum 5-year follow-up data. The overall reoperation rate was 9.0% (32 of 355). According to multivariable analysis, 5-year AOFAS scores were associated with number of PRP injections (correlation coefficient, 3.12 [95% CI, 2.36 to 3.89]; P < .001), BMI at baseline (correlation coefficient, -0.222 [95% CI, -0.363 to -0.082]; P = .002), and mean BMI change from baseline (correlation coefficient, -1.15 [95% CI, -1.32 to -0.98]; P < .001). When comparing number of PRP injections (0, 1-2, or ≥3), we found that patients who had serial PRP injection (≥3 with at least a 3-month interval between injections) had diminished functional and radiographic deterioration over time. Conclusion: Arthroscopic microfracture improved patient-reported and structural outcomes for patients with OLT at 5 years after surgery. Serial PRP injections and reduction in BMI from baseline were able to slow radiographic and functional deterioration. Future trials regarding the combination of microfracture and PRP in treatment of OLT should focus on the efficacy of longer term, intra-articular, serial injections of PRP instead of single injections.