This study analyses the health related quality of life (HRQOL) of advanced melanoma patients, in a randomised trial comparing bio-chemotherapy (bio-CT) versus chemotherapy (CT). The trial enrolled 178 patients and the median survival was not statistically different between the two arms. HRQOL was assessed at baseline and before each cycle of therapy, using the Rotterdam Symptom Checklist (RSCL) questionnaire completed with 140 patients. At baseline, overall quality of life and psychological distress scores were the most impaired, compared with the normal population. During treatment, the difference between the two arms in the changes from baseline was statistically significant (P=0.03) only in the overall quality of life score, with a decrease of 6.28 points in the bio-CT arm. The mean values decreased significantly in all domains in bio-CT arm, but only in activity level and physical symptom distress scores in the CT arm. Testing HRQOL variables and prognostic clinical factors in a Cox model, only the serum level of lactic dehydrogenase, baseline overall quality of life and the physical symptom distress scores remained significant independent prognostic factors for survival. A score of less than 75 points in the overall quality of life and in the physical symptom distress domains was associated with a Hazard Ratio (HR) of 2.31 (95% Confidence Interval (CI): 1.09-4.90) and 1.92 (95% CI: 1.10-3.36), respectively.