Background: Musculoskeletal disorders (MSDs) are a frequent cause of work disability, accounting for productivity losses in industrialized societies equivalent to 1.3% of the U.S. gross national product. Objective: To evaluate whether a population-based clinical program offered to patients with recent-inset work disability caused by MSDs is cost-effective. Design: Randomized controlled intervention study. The inclusion and follow-up periods each lasted 12 months. Setting: Three health districts in Madrid, Spain. Patients: All patients with MSD-related temporary work disability in 1998 and 1999. Intervention: The control group received standard primary care management, wit referral to specialized care if needed. The intervention group received a specific program, administered by rheumatologists, in which care was delivered during regular visits and included 3 main elements: education, protocol-based clinical management, and administrative duties. Measurements: Efficacy variables were 1) days of temporary work disability and 2) number of patients with permanent work disability. All analyses were done on an intention-to-treat basis. Results: 13 077 patients were included in the study, 7805 in the control group and 5272 in the intervention group, generating 16 297 episodes of MSD-related temporary work disability. These episodes were shorter in the intervention group than in the control group (man, 26 days compared with 41 days; P < 0.001), and the groups had similar numbers of episodes per patient. Fewer patients received long-term disability compensation in the intervention group (n = 38 [0.7%]) than in the control group (n = 99 [1.3%]) (P < 0.005). Direct and indirect costs were lower in the intervention group than in the control group. To save 1 day of temporary work disability, $6.00 had to be invested in the program. Each dollar invested generated a benefit of $11.00. The program's net benefit was in excess of $5 million. Limitations: The study was unblinded. Conclusions: Implementation of the program, offered to the general population, improves short- and long-term work disability outcomes and is cost-effective.