The study explored the interdependence of changes in oxygen uptake, quality of life and cancer-related side-effect fatigue during a 4-month exercise intervention. Participants were during adjuvant (curative) or palliative therapy and post-adjuvant therapy (finished within the previous 12 months). Aerobic exercise capacity (VO2 peak), quality of life and fatigue symptom (EORTC QLQ-C30) were obtained in 101 cancer patients (30-77 years). After initial examination, patients participated in supervised and/or home-based training interventions. Patients were re-examined after 16-20 weeks and stratified into 3 subgroups (terciles) with respect to the absolute change in VO2 peak. The ANCOVA, with significant covariate effect for pretest fatigue score (F(5,101) = 8.150, P < 0.001), indicated significant differences between groups in outcome measures (P < 0.001). Based on the absolute change of VO2 peak (1.9 ± 1.7; 1.8 ± 0.8; 5.7 ± 2.8 ml/kg/min) there were significant differences in the quality of life improvement (17.2 ± 15.1 vs. 4.8 ± 22.0 points, P < 0.05) and cancer-related fatigue reduction (-6.1 ± 30.7; -11.5 ± 20.9; -21.2 ± 21.4 points) between upper and lower tercile. The findings point towards a relationship of exercise capacity enhancement, quality of life improvement and fatigue symptom reduction during and shortly after cancer treatment.