Background Platelet-rich plasma (PRP) has the potential to improve tendon-bone healing. The evidence is still controversial as to whether PRP application after repair of medium-sized to large cuff tears leads to superior structural and clinical outcome, especially after single-row repair. Methods In a randomized study, 102 patients (PRP group, 52 patients; control group, 50 patients) with medium-sized and large degenerative posterosuperior tears were included for arthroscopic repair with a minimum follow-up of 2 years. Patients were evaluated with clinical scores (visual analog scale score, Constant-Murley score, University of California–Los Angeles score, and American Shoulder and Elbow Surgeons score) and ultrasound to assess retear and vascularity pattern of the cuff. Results Visual analog scale scores were significantly lower in the PRP group than in controls at 1 month, 3 months, and 6 months but not later. Constant-Murley scores were significantly better in the PRP group compared with controls at 12 and 24 months, whereas University of California–Los Angeles scores were significantly higher in the PRP group at 6 and 12 months ( P  < .05). The American Shoulder and Elbow Surgeons score in both groups was comparable at all the times. At 24 months, retear in the PRP group (n = 2; 3.8%) was significantly lower than in the control group (n = 10; 20%; P  = .01). The retear difference was significant only for large tears (PRP:control group, 1:6; P  = .03). Doppler ultrasound examination showed significant vascularity in the PRP group repair site at 3 months postoperatively ( P  < .05) and in peribursal tissue until 12 months. Conclusion Application of moderately concentrated PRP improves clinical and structural outcome in large cuff tears. PRP also enhances vascularity around the repair site in the early phase.