Work-related stress is widespread and can lead to long-term absenteeism and work disability. Cognitive-behavioral treatment (CBT) has demonstrated effectiveness in treating psychopathology but has only rarely been tested in clinical samples with work-related stress. A randomized controlled trial was conducted to investigate the efficacy of CBT-based stress management training (SMT). Eighty-two patients on sickness leave with work-related stress were randomly assigned to (a) individual SMT, (b) group SMT, or (c) care as usual (CAU). The SMT comprised 12 sessions conducted by a psychologist. Complaints of burnout and distress were measured at baseline, and at 4, 7, and 10 months. Absenteeism was measured during the whole research period. Across treatment conditions, complaints and sickness absence reduced considerably between baseline and 4 months. Thereafter, complaints remained approximately stable, whereas sickness absence further reduced. Hardly any significant group difference emerged, and no consistent pattern could be discerned in favor of any treatment condition. In subgroups with low depressive complaints, though, individual SMT resulted in larger reductions of some complaints than CAU. In conclusion, this study adds to the evidence that CBT-based interventions as currently practiced are not successful in treating patients with clinical levels of work-related stress.