Effective multidisciplinary rehabilitation programs supporting the return to work have become increasingly relevant for cancer survivors. In Germany, inpatient work-related medical rehabilitation programs consider treatment modules of work-related diagnostics, work-related functional capacity training, psychosocial groups, and intensified social counseling. The authors tested the effectiveness of a work-related medical rehabilitation program compared with conventional medical rehabilitation using a cluster-randomized multicenter trial (German Clinical Trial Register: DRKS00007770). In total, 484 patients with cancer were recruited at 4 rehabilitation centers. Patients at a center who started their rehabilitation in the same week represented a cluster. These clusters were randomly assigned using computer-generated randomization schedules either to an intervention group (IG) or to a control group (CG). The primary outcome was role functioning. Secondary outcomes were other quality-of-life domains and the return to work. In total, 425 patients (210 in the IG) were included in the analysis at the 3-month follow-up. There was no significant difference between the IG and CG in role functioning (b = 3.55; 95% CI, -1.18 to 8.29; P = .142). Participants in the IG reported better physical functioning (b = 5.99; 95% CI, 3.33-8.65; P < .001), less physical fatigue (b = -5.09; 95% CI, -9.62 to -0.56; P = .028), and less pain (b = -6.24; 95% CI, -11.24 to -1.23; P = .015). Work-related medical rehabilitation had no effect on the primary outcome compared with conventional medical rehabilitation but may enhance physical functioning and reduce physical fatigue and pain. © 2019 American Cancer Society.