In this study, 25 multiple myeloma (MM) patients at primary diagnosis and 18 MM patients at relapse or progressive disease (PD) were examined in order to investigate the incidence of P-glycoprotein (P-gp) expression at initial diagnosis and relapse or PD. Furthermore, P-gp expression in relation to VAD regimen response was determined. P-gp expression in the myeloma cells was determined using monoclonal antibody 4E3.16 and the rhodamine 123 functional test. The percentage of patients with P-gp overexpression at primary diagnosis ranged between 0 and 41% in the literature vs 32% in our study. The percentage of P-gp positive patients at relapse or PD ranged between 29 and 59% in the literature vs 33% in this analysis. All P-gp positive patients had a functional P-gp, ie a pumping P-gp. A significant difference concerning response (50 vs 58.3%) to VAD treatment and median survival (10 vs 12.5 months) between P-gp positive and P-gp negative patients could not be determined. Six of 12 P-gp negative MM patients at relapse or PD developed after VAD therapy a relapse combined with P-gp overexpression. These results do not confirm the suggestions that P-gp overexpression influences response to VAD treatment. However, the results described in the literature and our own emphasize the need for careful accompanying research programmes aimed at detecting the complexity of chemotherapy resistance in the light of developing a risk-adapting therapy for MM patients.