Context: Patellofemoral pain syndrome (PFPS) is one of the most common determinants of knee pain. The causes of PFPS are multifactorial, and most treatment approaches are conservative. There are many kinds of therapy for this syndrome, which are based on building strength, flexibility, proprioception, and endurance. Training is functional and progression is gradual. Our hypothesis is that total-body osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) focused on the management of somatic dysfunctions could be useful for managing the pain of patients with PFPS., Objective: To investigate the effect of OMTh on pain reduction in patients with PFPS., Methods: This pilot study was randomized, controlled, and single-blinded with 2 months of follow-up. Qualified participants were randomly assigned to 1 of 2 groups: OMTh group or placebo group. Each participant received either 4 sessions of OMTh or 4 sessions of manual placebo intervention that consisted of passive touching without joint mobilization in a protocolled order. A visual analogue scale (VAS) was used to assess general knee pain, peripatellar pain, pain after prolonged sitting, pain during the patellar compression test, and pain during stair ascent and descent. Pain assessment was performed before the baseline (T0), second (T1), third (T2), and fourth (T3) sessions, and follow-up (T4) was performed 8 weeks after T3., Results: Thirty-five participants were enrolled the study. The VAS score was significantly reduced and clinically relevant in the OMTh group after each treatment and after 2 months of follow-up. The change in the VAS score before each treatment indicates that the most improved areas at T1 compared with T0 were lumbar and sacral with improvements in 83% and 40% of patients, respectively. At T2 compared with T1, the most improved areas were cervical and sacral with improvements found in 58% and 36% of patients, respectively. The number of dysfunctions that were diagnosed decreased during the baseline to T3 period (40% change). The correlation analysis showed significant results for the dysfunction and the compression test at T2 (P=.01, ρ=0.543)., Conclusion: Significant differences in VAS scores were found between the OMTh and placebo groups. These findings underline how OMTh can lead to reduced pain in patients with PFPS.