Post-operative atrial fibrillation (POAF) is postulated as a complex interaction of different pathogenic factors, suggesting inflammatory processes as a main trigger of this particular type of atrial fibrillation. Therefore, the study sought to assess the impact of cellular immunity on the development of POAF. Comparing patients developing POAF to individuals free of POAF the fraction of CD4 CD28 T Lymphocytes was significantly higher in individuals developing POAF (11.1% POAF vs. 1.9% non-POAF; p < 0.001). CD4 CD28 cells were independently associated with the development of POAF with an adjusted odds ratio per one standard deviation of 4.89 (95% CI: 2.68-8.97; p < 0.001). Compared to N-terminal Pro-Brain Natriuretic Peptide, the fraction of CD4 CD28 cells demonstrated an increased discriminatory power for the development of POAF (NRI: 87.9%, p < 0.001; IDI: 30.9%, p < 0.001). Interestingly, a pre-operative statin-therapy was associated with a lower fraction of CD4 CD28 cells (p < 0.001) and showed an inverse association with POAF (p < 0.001). CD4 CD28 cells proved to be predictive for the development of POAF after cardiac surgery. Our results potentially indicate an auto-immune impact of this preexisting, highly cytotoxic T cell subset in the pathogenesis of POAF, which might be modified via the anti-inflammatory potential of a pre-operative statin-therapy.