Objective: Oral lichen planus (OLP) is a chronic mucocutaneous disease with unknown etiology. Oral lichenoid reactions (OLRs) comprise a family of lesions with different recognized etiologies. OLR lesions have clinical and histopathologic characteristics similar to those of OLP, although their management is different from that for OLP. Discrimination between OLP and OLR has always been a major challenge for both clinicians and pathologists. For this purpose, this study evaluated mast cells in the lamina propria of OLP and OLR lesional tissues. Method and Materials: The study was performed on 23 cases of OLP and 23 cases of OLR categorized based on clinical examination, histopathology evaluation, and history in accordance with WHO definitions of OLP. Mast cells in the reticular layer of the lamina propria for OLP and OLR lesions were evaluated both quantitatively (total number) and qualitatively (degranulation status) using light microscopy. Two staining methods-toluidine blue (histochemistry) and antitryptase (immunohistochemistry)-were used for identification and mapping of the mast cells. Results: No significant difference was observed in the total number of mast cells between the two disease groups (P = .74 toluidine blue, P = .47 antitryptase). A statistically significant difference was noted between the number of degranulated mast cells of OLP and OLR lesions with only toluidine blue stain (P .001 toluidine blue, P = .14 antitryptase). A statistically significant difference in the ratio of degranulated mast cells to the total population was observed between OLP and OLR lesions with both staining methods (P .001 for both methods). Conclusion: The observed difference in the ratio of degranulated to total mast cell population in the reticular zone of the lamina propria may be a useful criterion for histopathologic distinction between OLP and OLR. This may also explain the different therapeutic approaches toward these two lesions. Keywords: differentiating, histochemistry, immunohistochemistry, mast cell, oral lichenoid reaction, oral lichen planus