Given the survival advantage, high-dose therapy (HDT) remains the standard of care for patients with multiple myeloma eligible for the procedure. For those undergoing HDT, initial therapy aimed at reducing tumor burden is given prior to stem cell harvest. Various regimens, mostly variations of VAD (vincristine, doxorubicin, dexamethasone), are used for induction therapy. We retrospectively evaluated if single agent dexamethasone would be an effective induction therapy, given that it is the most active drug in these combinations. A total of 35 patients who received induction therapy with dexamethasone alone were compared to a similar group of 72 patients who received VAD as the initial therapy. We found a 63% response rate with dexamethasone compared to 74% with VAD (P=0.25). Including minimal responses, the overall response rate for Dex and VAD was 74 and 86%, respectively (P=0.13). The overall and complete response rates to transplant, respectively, were 97 and 26% for the dexamethasone group and 100 and 39% for the VAD group; P=0.33 and 0.18. No significant differences were observed in the progression-free and overall survival at 1 year post transplant. Single agent dexamethasone appears to be an effective alternative to VAD for induction therapy prior to HDT in myeloma.