Introduction: Clinical differentiation between bipolar disorder (BD) and major depressive disorder (MDD) is difficult. Research has therefore focused on discriminatory biological markers. Previous studies in MDD reported T cell deficits, while the limited studies in BD reported T cell activation. Studies directly comparing circulating numbers of T cells and T cell subsets between BD and MDD are lacking. The studies in the MOODINFLAME consortium make such a comparison possible. Methods: The number of circulating leukocyte populations (lymphocytes, monocytes, NK cells, B cells, T cells, CD3+CD8+ T cytotoxic cells, CD3+CD4+ T helper cells, Th1, Th2, Th17 and T regulatory cells) was determined using FACS technology in a cohort of 83 euthymic BD patients, 8 BD patients with a current mood episode and 165 healthy controls (HC). Data were compared to those of 34 moderately and 56 severely depressed MDD patients. Results: Compared to MDD patients, BD patients showed significantly increased levels of Th17, Th2, Th1 and T regulatory cells (all p < .02). In BD patients, levels of Th17 and T regulatory cells were increased compared to HC (p = .03, p = .02, respectively), while MDD patients showed decreased levels of Th17 and Th2 compared to HC (p = .03, p = .01, respectively). Of the various medications only SSRI/SNRI usage could explain part of the Th2 decrease in MDD. Conclusion: This study shows CD4+ T helper cell deficits in MDD patients, while normal or even raised levels of these cells were found in BD patients. The differences in CD4+ T helper cell differentiation was most outspoken for Th17 cells.Keywords: Bipolar disorder; Leukocyte subset; Major depressive disorder; T cell defect; T helper cell differentiation; Th17; Th2.