The fast but short-lasting improvement of depressive symptoms by sleep deprivation (SD) in about 60% of patients with a major depressive disorder is well established, but the mechanisms of action are still not clear. Recent studies suggest that changes in non rapid eye movement (NREM) sleep, especially in slow wave activity (SWA), could be associated with the therapeutic outcome of SD. In the current study, spectral analysis of NREM sleep EEG directly prior to SD was performed to determine if automatically derived sleep parameters predict SD response. Sixteen pair matched and drug free patients with a major depressive disorder, 8 SD responders and 8 non-responders (response criterion: 50% reduction on the 6-item HAMD score), were included. Average EEG spectral power was calculated for the whole night before SD and for single NREM episodes. While whole-night averages of spectral power did not differ significantly between subgroups, SD responders showed a steady decrease of SWA across successive NREM episodes, whereas in non-responders an increase from the first to the second episode was observed. The different distribution of SWA was significantly expressed in the delta sleep ratio (quotient of SWA in the first to the second NREM episode). In conclusion, a high delta sleep ratio is a positive predictor for SD response. Referred to psycho- and pharmacotherapeutic results it is hypothesized that low and high values of the delta sleep ratio characterize subgroups of depressed patients with different neurobiological alterations, which could be relevant for further scientific and therapeutic approaches.