Earlier studies showing a negative impact of anaemia on quality of life (QOL) lack adequate adjustment for confounding factors such as disease stage and tumour response. We examined the impact of haemoglobin concentration on QOL scores of 745 multiple myeloma patients followed from diagnosis, adjusting for objective disease parameters. Data from two Nordic studies with the EORTC QLQ-C30 questionnaire were analysed using linear regression analysis. Haemoglobin was independently related only to fatigue at baseline (P = 0.001) and at 12 months (P = 0.010). In multivariate analysis, extent of skeletal disease was at least as strong a predictor for fatigue at diagnosis as haemoglobin and was also related to other important QOL scores such as physical functioning, role functioning, global QOL and pain (P < 0.001). At 12 months' follow-up, response to therapy was related to physical functioning (P < 0.001) and pain (P = 0.001). In conclusion, haemoglobin and extent of skeletal disease were both predictors for fatigue in patients with newly diagnosed multiple myeloma, but extent of skeletal disease was also associated with other important QOL scores. During follow-up, response to therapy emerged as an important predictor variable. When examining the effect of haemoglobin on QOL, it is essential to adjust for disease parameters and response to therapy in order not to overestimate the impact of haemoglobin on QOL. Our findings imply that uncontrolled studies on the effect of erythropoietin (EPO) in cancer patients may be making exaggerated claims for the effect of EPO on QOL.