Background: Depression is a mental health disorder characterized by persistent feelings of sadness, hopelessness, and a loss of interest or pleasure in activities. The present study was conducted to assess efficacy of ketamine versus thiopentone-assisted modified electroconvulsive therapy in major depression. Materials & Methods: 56 patients with major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders-IV Text Revision) of both genderswere divided into two groups of 28 each. Group I received ketamine and group II received thiopentone as anesthetic agent. Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BDI) were recorded at baseline, completion of ECT and at 6 weeks follow up. Results: Themean number of ECT sessions was 5.9 in group I and 8.2 in group II. EEG seizure duration was 50.7 seconds in group I and 43.6 seconds in group II. Stimulus intensity was 82.1mCin group I and 92.8mC in group II. The difference was significant (P< 0.05). In group I and group II, HAM-D score at baseline was 29.5and 32.2, at completion of ECT was 1.9 and 1.8 and at 6 weeks follow up was 0.21 and 0.25 respectively. BDI score at baseline was 51.2 and 52.8, at completion of ECT was 6.5 and 7.2 and at 6 weeks follow up was 0.78 and 1.5 respectively. MMSE score at baseline was 27.4 and 27.9, at completion of ECT was 5.7 and 6.9, and at 6 weeks follow up was 1.3 and 2.7 respectively. Side effects were headache in 7 and 9, nausea/vomiting in 4and 1, emergence reactions in 3 and 1, and delirium in 2and 0 in group I and group II respectively. Conclusion: Ketamine anesthesia produced a quick recovery from depression symptoms, suggesting that it is a preferable choice for depressed individuals, particularly in cases where a quick response is required.