Context: The effects of an exercise program (EP) for the treatment of patellofemoral pain syndrome (PFPS) are well known. However, the effects of osteopathic manipulative treatment (OMT) are unclear. Objective: To evaluate the effects of OMT versus EP on knee pain, functionality, plantar pressure in middle foot (PPMF), posterior thigh flexibility (PTF), and range of motion of hip extension in runners with PFPS. Design: This is a randomized controlled trial. Setting: Human performance laboratory. Participants: A total of 82 runners with PFPS participated in this study. Interventions: The participants were randomized into 3 groups: OMT, EP, and control group. The OMT group received joint manipulation and myofascial release in the lumbar spine, hip, sacroiliac joint, knee, and ankle regions. The EP group performed specific exercises for lower limbs. The control group received no intervention. Main Outcome Measures: The main evaluations were pain through the visual analog scale, functionality through the Lysholm Knee Scoring Scale, dynamic knee valgus through the step-down test, PPMF through static baropodometry, PTF through the sit and reach test, and range of motion through fleximetry. The evaluations were performed before the interventions, after the 6 interventions, and at 30-day follow-up. Results: There was a significant pain decrease in the OMT and EP groups when compared with the control group. OMT group showed increased functionality, decreased PPMF, and increased PTF. The range of motion for hip extension increased only in the EP group. Conclusion: Both OMT and EP are effective in treating runners with PFPS.