Objectives: The main objectives of the study were to determine the expressions of the cytotoxic molecules granulysin (GNLY) and perforin-2 (P2) in the lymphocytes' subpopulations of the peripheral venous blood and in the lesional and nonlesional skin of patients with psoriasis and lichen planus. Patients and Methods: The expressions of GNLY+ and P2+ cells in the peripheral blood were investigated by simultaneous labelling of intracellular and surface markers in monocytes and in different lymphocytes' subpopulations by immunofluorescence, with a flow cytometer results reading. By single immunohistochemistry, we investigated the expressions and distribution of GNLY+ and P2+ cells, while by double immunohistochemistry we analyzed the expressions and distribution of CD8+GNLY+ and CD56+GNLY+ cells in both sections of lesional and nonlesional skin of patients with psoriasis and lichen planus in relation to the healthy skin of the control group. Results: The frequency of GNLY+ cells was statistically significantly higher in all cells, and of P2+ cells in monocytes (CD14+) of peripheral blood of both psoriasis patients groups and patients with lichen planus compared to the control group, while the percentage of GNLY+, CD3+CD8+GNLY+, CD3+CD56+GNLY+ and CD14+P2+ cells statistically significantly differed in the peripheral blood of patients with severe and mild psoriasis also. The psoriasis severity statistically significantly correlated with the proportions of GNLY+, CD3+CD8+GNLY+, CD3+CD56+GNLY+ and CD14+P2+ cells in the peripheral venous blood of psoriasis patients. Conclusion: The increased proportion of GNLY+ and P2+ cells in peripheral venous blood and in lesional and nonlesional skin of patients with psoriasis and lichen planus, as well as a positive correlation of psoriasis severity with the frequency of GNLY+ and P2+ cells suggest that cytotoxic mechanisms mediated by GNLY and P2 contribute to the pathogenesis of these diseases at the systemic and the local level. Therefore, GNLY and P2 could be used in the future as biomarkers for the successful assessment of psoriasis severity and activity