Musculoskeletal disorders (MSDs) are among the most common cause for reduced work capacity and sick leave. Workplace health promotion programs are often neither tailored to the workplace nor the individual needs of the employees. To counteract lacking intersectional care, this four-year randomized controlled trial (RCT) aimed to investigate the effects of modular coordinating case management (treatment group) compared to supported self-management (control group) on MSD specific sick leave days (routine data), workability (WAI), self-efficacy (self-efficacy scale), and pain (German pain questionnaire, GPQ). The study network comprised 22 companies, 15 company health insurance funds, and 12 pension funds in Germany. Overall, 852 participants (Module A/early intervention: n = 651, Module B/rehabilitation: n = 190, Module C/reintegration: n = 10) participated. Both groups achieved fewer sick leave days, higher workability, and less pain (p < 0.0001) at follow-up compared to baseline. At follow-up, the coordinating case management group showed fewer disability days (GPQ), lower disability scores (GPQ), and lower pain intensities (GPQ) than the supported self-management group (p < 0.05), but no superiority regarding MSD specific sick leave days, workability, nor self-efficacy. Module A showed more comprehensive differences. The accompanying process evaluation shows barriers and facilitators for the implementation of the program, especially in a RCT setting.