Lichenoid drug eruption (LDE) shares similar features with lichen planus (LP), that could reflect the same pathogenesis. In LP, an autoimmune attack is accepted and cytotoxic T-lymphocytes (CD8+) predominate, especially in late lesions. Apoptosis of keratinocytes may be mediated by CD8+ T and NK cells in two distinct ways: by the release of cytotoxic molecules such as perforin and granzyme B or by the Fas/FasL system. The immunological mechanisms involved in LDE are not yet fully established. Investigate immunohistological features in LP and LDE to add clues to better understand their pathogenesis. Twenty-two patients fulfilled all clinical, laboratory, histopathological, and follow-up features of lichen planus (n = 16) and lichenoid drug eruption (n = 6). Classic histological features favoring LP or LDE were evaluated by two observers. HAM56, MAC387, UCHL-1, OPD4, CD8, Granzyme B, Perforin, and ICAM-1 antibodies were used to decorate the immune infiltrate. Results were analyzed through Pearson correlation, Student's t-test, and linear discriminant analysis. A higher number of necrotic keratinocytes as well as plasma cells and eosinophils within inflammatory cells were associated with LDE diagnosis. Only in LDE, a correlation was found between the number of T and CD8+ cells and between the number of granzyme B+ cells and apoptotic keratinocytes. Our findings suggest a more important role of CD8+ granzyme B-containing cells in LDE group, being its synthesis associated with more intense apoptosis. So, LP and LDE may have a somewhat distinct pathogenesis.511199-205