Treatment of malignant melanoma with IFN-α has been associated with significant side-effects. The aim of this retrospective monocentric non-randomized study was first to evaluate the impact on quality of life (QOL) in 30 melanoma patients treated with once weekly 2 μg/kg PEG-IFN-α2b for 18 months, and second to examine whether there is a difference in patients' and physicians' perception of QOL. Data on QOL were collected by means of the EORTC QLQ-C30 questionnaire completed by the patient before consultation at baseline and every three months during treatment. A second questionnaire was filled out independently by the physician, based on the consultation and patient file. All data were routinely collected in an outpatient care unit. At baseline, patients had more favorable mean values on almost all dimensions of the EORTC QLQ-C30 than follow-up assessments. In comparison to published low-dose IFN-α2a data, once weekly 2 μg/kg PEG-IFN-α2b was associated with stronger impairment in most QOL single dimensions but with almost no differences regarding the global health status. QOL documented by physicians was significantly higher than QOL from the patients' questionnaires in all QOL dimensions (p<0.05). PEG-IFN-α2b has measurable effects on QOL. Measuring QOL based only on physicians' patient files without explicitly determining patients' assessments leads to a profound underestimation of impairment of QOL.