Thalidomide (T) or bortezomib (B) in combination with melphalan plus prednisone (MP) is superior to MP as first line therapy for previously untreated myeloma. However, direct head-to-head comparison of Melphalan, Prednisone plus Bortezomib (MPB) versus Melphalan, Prednisone plus Thalidomide (MPT) is lacking. We performed an indirect meta-analysis to assess the treatment effects of MPB versus MPT via common comparator MP using the systematic review and meta-analytical techniques. A comprehensive literature search (MEDLINE and gray literature) was undertaken. Systematic review was performed as per the Cochrane Collaboration recommendations. Initial search yielded 1,013 citations, of which six randomized controlled trials (RCTs) enrolling 2,798 patients met the inclusion criteria. Comparison of MPT versus MP (five RCTs) showed no survival difference [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.64–1.05] but a statistically significant difference in event-free survival favoring MPT (HR 0.66, 95% CI 0.56–0.77) without excessive treatment-related mortality [risk ratio (RR) 1.11, 95% CI 0.64–1.92]. Comparison of MPB vs. MP (one RCT) showed a statistically significant benefit for survival (HR 0.65, 95% CI 0.51–0.84) and event-free survival (HR 0.48, 95% CI 0.37–0.63) without difference in treatment-related mortality (RR 0.42, 95% CI 0.11–1.63) with MPB. The indirect comparison of MPB versus MPT showed no difference between MPB versus MPT for all outcomes but a significant benefit for complete response (RR 2.34, 95% CI 1.12–4.90), and grade III/IV adverse events (RR 0.53, 95% CI 0.38–0.73) favoring MPB. There is an uncertainty about definitive superiority of one type of regimen over the other. Therefore, direct head-to-head comparison between these competing regimens is warranted. Am. J. Hematol., 2011. © 2010 Wiley-Liss, Inc.