The extent to which self-assessed work ability collected during treatment can predict return-to-work in cancer patients is unknown. In this prospective study, we consecutively included employed cancer patients who underwent treatment with curative intent at 6 months following the first day of sick leave. Work ability data (scores 0-10), clinical and sociodemographic data were collected at 6 months, while return-to-work was measured at 6, 12 and 18 months. Most of the 195 patients had been diagnosed with breast cancer (26%), cancer of the female genitals (22%) or genitourological cancer (22%). Mean current work ability scores improved significantly over time from 4.6 at 6 months to 6.3 and 6.7 at 12 and 18 months, respectively. Patients with haematological cancers and those who received chemotherapy showed the lowest work ability scores, while patients with cancer of urogenital tract or with gastrointestinal cancer had the highest scores. Work ability at 6 months strongly predicted return-to-work at 18 months, after correction for the influence of age and treatment (hazard ratio=1.37, CI 1.27-1.48). We conclude that self-assessed work ability is an important factor in the return-to-work process of cancer patients independent of age and clinical factors.