BACKGROUND& AIMS: Lymphocytic is ill defined and inflammatory lesions of esophageal squamous epithelium are believed to show non-specific histological changes. This study was performed to investigate the histological and molecular criteria in esophagitis. METHODS: We collected 33 biopsies from 28 patients with esophagitis, which were diagnosed between 2010 and 2012 (17 men and 11 women, mean age = 60,8 and 61,1 years, respectively). Grading was performed by the number of lymphocytes (50/HPF cut off value) and according to Purdy et al. The inflammatory infiltrate was characterized by using the XTRACT robot (STRATIFYER, Cologne, Germany), quantitative real-time-PCR (FOXP3, CXCL9, CXCL13, IGHM, CD3, CD4 and CD8) and immunohistochemistry (CD4, CD8, TIA, GranzymB and Caspase 3). Spearman rank test was used to calculate the correlation between these parameters. RESULTS: Apoptoses could be detected in 83% of severe cases (15/18) and in 47% of mild cases (7/15) without differences between the two grading systems. High levels of cytotoxic T-cells were present in 80% of severe cases with apoptoses (12/15) and in 5 cases without visible apoptoses in H&E stain, mostly mild cases. The overall number of lymphocytes correlated with the number of apoptoses (p = 0,002) and the number of CD8 positive lymphocytes (p = 0,005). Cases with apoptoses showed high levels of CD8 positive lymphocytes. A positive correlation between spongiosis and levels of cytotoxic T-cells could be demonstrated (p = ,0,0001). Evaluation of clinical data revealed a correlation between high levels of cytotoxic lymphocytes and a wavey mucosal surface (p = 0,025), reddening of esophageal epithelium (p = 0,017) and a stipplelike exsudate (p = 0,015). Within the group with apoptoses a strong correlation between cytotoxic T-cells (= CD8) and regulatory T-cells (= FOXP3) (p = ,0,0001) was found. Expression of CXCL9 correlated with the expression of CD4 and CD8 (p = 0,05 and p = 0,0042, respectively). CONCLUSIONS: Our data suggest that the term lymphocytic esophagitis should only be used as an umbrella-term in several diseases and therefore we suggest lymphocyte-rich esophagitis to be used for further subdivisions. Two different subgroups of this variant of chronic can be distinguished: Lymphocyte-rich with apoptosis (LEA) and with no apoptosis (LENA). Apoptotic keratinocytes are usefull in grading LEA, as they can be found in large numbers predominantely in severe forms. The number and localization of apoptoses distinguishes esophageal Crohn's disease and lichen planus from LEA. Further studies should focus on the question, whether our findings are a hint to an autoimmunologic mechanism or not.