Many regimens containing novel drugs have been developed for multiple myeloma (MM). It is not yet clear whether some of the novel agents are better than others. In a retrospective study, we have analyzed the outcomes of patients with first relapse of MM treated with thalidomide-based (T) regimens (n=105) or bortezomib-based (B) regimens (n=106). Both T and B groups were comparable regarding basic clinical parameters and first-line therapies. Combination of thalidomide with an alkylating drug (A) and dexamethasone (D) was used in 91 cases, T with D in five cases, and T alone in nine cases. A combination of bortezomib with A and D was used in 58 patients, B with D or A in 40 patients, and B alone in eight patients. In the T group, ORR was 51%, median TTP from the start of treatment for relapse of 13.1 months, and median OS of 30.4 months. In the B group, ORR was 50% with median TTP of 16.7 months and median OS of 37.2 months. No significant differences in ORR (p=0.774), TTP (p=0.207), or OS (p=0.889) were observed between the two groups. In conclusion, T- and B-based regimens appear to be equally effective in the treatment of first MM relapse.