The aim of the present study was to test whether psychological distress and personality variables are independently associated with health-related quality of life (HRQOL) in colorectal cancer patients, after adjusting for age, gender, education and disease severity. In a cross-sectional study of 162 colorectal cancer patients (response rate 65.6%), the following self-report instruments were administered: the Symptom Distress Checklist-90-R, the Sense of Coherence scale, the Life Style Index and the Hostility and Direction of Hostility Questionnaire. The outcome measures were the four components of the WHO Quality of Life Instrument, Short Form. We used hierarchical regressions to determine whether psychological distress mediates the relationship of personality and disease parameters with HRQOL. The overall proportion of the variance in the four components of HRQOL explained by our regression models ranged from 28.1 to 44.4%. Psychological distress was an independent correlate of HRQOL, associated with physical (p<0005), mental (p<0.05) and social relationships HRQOL (p<0.02). Personality variables were associated with HRQOL independent of psychological distress and disease severity. Sense of coherence and denial defense were positively associated with all aspects of HRQOL independent of psychological distress and disease parameters (p-values ranging from p<0.05 to p<0.0005). Hostility (p<0.01) and repression defense (p=0.024) were also independently but negatively associated with physical HRQOL. In colorectal cancer patients, psychological distress is associated with HRQOL independent of disease parameters but personality variables are also associated with HRQOL independent of disease severity and psychological distress, and this could be relevant to psychological interventions.