Associations of functional status (as measured with the Karnofsky Index), depressive symptoms (as assessed with the Beck Depression Inventory), and sociodemographic characteristics with health-related quality of life (HrQoL; measured with the EORTC Quality of Life Questionnaire QLQ-C30) were assessed in 170 recently diagnosed cancer patients. A better functional status (p<0.001) and a lower level of depressive symptoms (p<0.001) were associated with better HrQoL. In addition, an interaction effect of functional status with HrQoL was found (p<0.001), indicating that stronger functional impairments were related to lower HrQoL in patients with low and average levels of depressive symptoms, but not in those with high levels of depressive symptoms. Associations of HrQoL with sociodemographic variables were not significant. It is concluded that functional decline does not additionally impair HrQoL when patients already have elevated levels of depressive symptoms.