We evaluated the risk factors for infection of 367 consecutive myeloma patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT). Examination of bone marrow iron stores (BMIS) prior to ASCT was used to evaluate body iron stores. Other variables included age, sex, active smoking, myeloma remission status, severity of mucositis and duration of severe neutropenia post-ASCT (< 100 absolute neutrophils counts (ANC)/μl). Median age was 56 years; 61% of patients were males. 140 episodes of severe infections occurred in 116 patients, including bacteremia (73), pneumonia (40), severe colitis (25) and bacteremia with septic shock (two). The infection incidence per 1000 days at risk was 45.2. Pre-ASCT risk factors for severe infection by univariate analysis were increased BMIS (OR= 2.686; 95% CI 1.707–4.226; P< 0.0001), smoking (OR= 1.565; 95% CI 1.005–2.437; P= 0.0474) and male gender (OR= 1.624; 95% CI 1.019–2.589; P= 0.0414). Increased BMIS (OR= 2.716; 95% CI 1.720–4.287; P< 0.0001) and smoking (OR= 1.714; 95% CI 1.081–2.718; P= 0.022) remained significant by multivariate analysis. Duration of ANC< 100 μ/l (OR= 1.129; 95% CI 1.039–1.226; P= 0.0069 and OR= 1.127; 95% CI 1.038–1.224; P= 0.0045 by both univariate and multivariate analysis, respectively) was the only post-ASCT risk factor for infection. Increased pre-transplant BMIS and smoking are significant predictors of severe infection after myeloablative chemotherapy followed by ASCT in myeloma patients.