Background: Cytology is a diagnostic technique used to evaluate the properties of individual cells. Tzanck smear is a quick, simple, sensitive cytology procedure that can be done with little patient discomfort and expense. Objective: The purpose of this study was to determine the value of Tzanck smear in evaluating vesiculobullous illnesses and active genital herpes in relation to clinical diagnosis. Methods: A cross-sectional study was carried out to determine the value of Tzanck smear in evaluating various vesiculobullous skin lesions in comparison to clinical diagnosis. For statistical analysis, the Fisher's exact test was applied. Results: The majority of the 70 patients evaluated had viral infections or auto immune vesiculobullous diseases. On cytology, all patients with viral infection had multinucleated giant cells, and all patients with pemphigus had a large number of acantholytic cells as well as an inflammatory infiltrate. All of the patients with bullous pemphigoid had a significant number of eosinophils. The presence of acantholytic cells, multinucleate large cells, and eosinophils had a highly significant connection with clinical diagnosis. Conclusion: Tzanck smear, while not a replacement for traditional histology, can aid in establishing the clinical diagnosis with ease and speed.