Patients with multiple myeloma (MM) refractory to alkylating agents frequently express P-glycoprotein (Pgp), which is associated with the multidrug resistance (MDR) phenotype. We have conducted a randomized phase II/III study of the MDR reversal agent cyclosporin A combined with VAD (vincristine, doxorubicin, dexamethasone) compared with standard VAD in patients with MM stage IIA/IIIA who were refractory to or progressive after treatment with alkylating agents. Out of 81 patients who were randomized, 75 were eligible and evaluable: 34 in the VAD + cyclosporin A arm versus 41 in the VAD arm. Toxicities of grade 2–3 were observed more often with VAD + cyclosporin A than with VAD only: nausea (30% versus 8%, P = 0·015), mucositis (18% versus 5%, P = 0·13), infection (45% versus 35%, P = 0·50). The treatment results were similar in the two arms: 53% versus 49% responded [95% CI (−18·5%, 26·9%)]. The median progression-free survival (PFS) was 8·6 months (VAD + cyclosporin A) versus 5·8 months (VAD): [log rank P = 0·16, hazard ratio = 0·71, 95% CI (0·44, 1·15)], and median overall survival was 13 months versus 14·6 months [log rank P = 0·89, hazard ratio = 0·96, 95% CI (0·62, 1·72)]. The cause of death was progressive disease (85%), toxicity (10%) or other (5%). Bone marrow analysis performed in 23 patients showed that the response rate was 67% in Pgp-positive versus 55% in Pgp-negative patients. Cyclosporin A combined with VAD is relatively well tolerated. There is no effect of cyclosporin A on the overall response rate, PFS and overall survival with VAD.