Background: Recent studies have revealed that recurrent depressive disorders (rDD) are linked with dysregulation of the immune system. Previous studies have found that manganese superoxide dismutase (MnSOD, SOD2) may be a key inflammatory enzyme involved in this disorder. The purpose of this study was to determine the mRNA and protein levels of MnSOD in patients with rDD and to define the relationship between serum MnSOD levels and cognitive performance. Methods: The study comprised 236 subjects, which included patients with rDD (n = 131) and healthy subjects (n = 105, healthy control group, HC). Assessment of cognitive function was based on performance on the Trail Making test (TMT), the Stroop test, the Verbal Fluency test (VFT) and the Auditory Verbal Learning test (AVLT). Results: MnSOD gene expression at mRNA and protein level was significantly lower in rDD patients than in the HC group (p < 0.01). In the rDD and HC groups separately, there were no statistically significant associations between mRNA and protein expression levels of the MnSOD and psychological tests. In the total study group (n = 236), there was a statistically significant correlation between both MnSOD gene levels and the following tests (p < 0.01): the TMT parts A and B (negative correlation), the Stroop test parts RCNb (reading color names in black) and NCWd (naming color of word - different; negative correlation), the VFT (positive correlation) and the AVLT (positive correlation). Conclusions: Our study provides evidence that the MnSOD enzyme-coding gene and MnSOD expression are important for the regulation of cognitive functioning.