Background: Lenalidomide plus Dexamethasone (Len-Dex) and VAD (Vincristine, Doxorubicin and Dexamethasone) regimen are the two common drug therapies employed in the treatment of Multiple myeloma.Objectives: To compare the efficacy of Len-Dex versus VAD regimen based on complete remission achieved with treatment in newly diagnosed cases of multiple myeloma in a tertiary care hospital in Kerala.Methods: Eighty patients (forty in each group) of newly diagnosed cases of multiple myeloma, who were willing to give the informed consent, were included in the study. Patients were allocated by the treating physician to two groups; one group was given Len-Dex (lenalidomide + dexamethasone) regimen and the other VAD (Vincristine, Adriamycin, Dexamethasone) regimen. A total of six cycles were given for both groups. Their baseline investigations and follow up investigations were collected at regular intervals, based on these values, the outcome was classified as partial remission and complete remission and the results were compared and analyzed.Results: Among the forty patients in each group, 17 (38%) on VAD regimen and 28 (62%) on Len-Dex regimen achieved complete remission. The statistical analysis was done using chi square test (χ2= 6.13, df= 1, p= 0.01) which showed statistically significant difference.Conclusions: The study showed that the efficacy of Lenalidomide-Dexamethasone (Len-Dex) combination therapy is clearly higher than that of VAD regimen among the study population. The overall efficacy of Len-Dex combination is 70% and that of VAD regimen is only 42.5%.