OBJECTIVE: Guidelines include manual therapy and exercise for subacromial shoulder pain, but there is low certainty for these recommendations. Here, we evaluated if adding manual therapy to a resistance exercise program improved patient outcomes. DESIGN: Randomized parallel controlled clinical trial. METHODS: Individuals with subacromial pain syndrome (N = 93) were randomized to exercise (EX; n = 41) or exercise plus spine and shoulder manual therapy (EX+MT; n = 52). Primary outcome of Disabilities of the Arm, Shoulder and Hand (DASH) and secondary outcome of satisfaction with shoulder use (Satisfaction-shoulder) at baseline, 2, 4, 6, 26, and 52 weeks were compared between groups. Secondary outcomes of additional health care use were compared at 26 and 52 weeks and GROC success (≥“moderately better”) at 2, 4, 6, 26, and 52 week prevalence were compared between groups. RESULTS: The EX+MT group had better DASH scores at 26 weeks (mean difference = 4.9 [95% CI: 9.8, 0.1], P = 0.047) and 52 weeks (mean difference = 6.7 [95% CI: 11.4, 2.1], P = 0.005) compared to the EX group. The EX+MT group had better Satisfaction-shoulder scores at 26 weeks (mean difference = 0.8 [95% CI: 0.2, 1.5], P = 0.012) and 52 weeks (mean difference = 1.2 [95% CI: 0.5, 1.8], P<0.001) compared to the EX group. Higher GROC success was found at 26 and 52 weeks in EX+MT ( P<0.05). There were no differences for additional health care use ( P>0.171). CONCLUSION: Manual therapy added to a resistance exercise program improved long-term shoulder disability, satisfaction, and perceived benefit in patients with subacromial pain. Both groups had improved outcomes over time, with greater effects for the EX+MT group at 26 and 52 weeks. JOSPT Open 2024;2(1):29-48. Epub 11 December 2023. doi:10.2519/josptopen.2023.1134