Vincristine-adriamycin-dexamethasone (VAD) regimen with intermittent high-dose dexamethasone (HD) has been used as primary chemotherapy for multiple myeloma (MM) patients who are candidates for high-dose therapy or present with renal failure. However, dexamethasone increases the risk of infection in MM patients. We retrospectively evaluated treatment efficacy and infectious events in MM patients undergoing VAD with or without HD. Seventy-seven consecutive patients who received VAD without HD (n = 37) or VAD-HD (n = 40) at our institution were assessed. Characteristics of patients and VAD regimens were retrospectively analyzed to detect correlations with the incidence of infections. During 218 VAD cycles, 48 infectious episodes were documented in 39 patients. Of these, 32 episodes in 26 patients were severe (grade ≥ 3). By analyzing each patient, VAD-HD was associated with risk of all-grade and severe bacterial infection, while International Staging System stage ≥ 2 was independently correlated with severe bacterial infection. Response rates after two cycles were comparable between the 2 VAD regimens. In conclusion, risk of infection is lower in VAD without HD than in VAD-HD, and the clinical response is equivalent. VAD-HD should thus be avoided for MM patients with high risk of infection.