Objectives To support return to work (RTW) among cancer patients, a multidisciplinary rehabilitation programme was developed which combined occupational counselling with a supervised physical exercise programme during chemotherapy. The aim was to investigate RTW rates of cancer patients and to evaluate changes in work-related quality of life and physical outcomes. Design Longitudinal prospective intervention study using a one-group design. Setting Two hospitals in the Netherlands. Participants Of the eligible patients, 56% participated; 93 patients with a primary diagnosis of cancer receiving chemotherapy and on sick leave were included. Patients completed questionnaires on RTW, the importance of work, work ability (WAI), RTW self-efficacy, fatigue (MFI), and quality of life (EORTC QLQ C-30) at baseline and 6, 12 and 18 months follow-up. Before and after the exercise programme 1-repetition maximum (1RM) muscle strength and cardiorespiratory fitness (VO 2 peak) were assessed. Results Six months after the start of a multidisciplinary rehabilitation programme that combined occupational counselling with a supervised physical exercise programme, 59% of the cancer patients returned to work, 86% at 12 months and 83% at 18 months. In addition, significant improvements (p<0.05) in the importance of work, work ability, RTW self-efficacy, and quality of life were observed, whereas fatigue levels were significantly reduced. After completing the exercise programme, 1RM muscle strength was significantly increased but there was no improvement in VO 2 peak level. Conclusions RTW rates of cancer patients were high after completion of the multidisciplinary rehabilitation programme. A multidisciplinary rehabilitation programme which combines occupational counselling with a supervised physical exercise programme is likely to result in RTW, reduced fatigue and increased importance of work, work ability, and quality of life.