Lectins are glycoproteins that bind to specific carbohydrate groups on cell surfaces. Peanut lectin (PNA) binds to carbohydrates on the membranes of normal keratinocytes. Recently, some authors have proposed that PNA may be a useful marker to help differentiate keratoacanthomas from well-differentiated squamous cell carcinomas of the skin. We studied a total of 34 skin biopsy specimens, including 11 keratoacanthomas, 15 well-differentiated squamous cell carcinomas, and 8 poorly differentiated squamous cell carcinomas, using peanut lectin with the avidin-biotin complex (ABC) peroxidase technique. All keratoacanthomas demonstrated uniform positive membrane staining of keratinocytes, which was identical to PNA staining in normal skin. Keratinocytes in 80% of the well-differentiated squamous cell carcinomas and keratinocytes in all the poorly differentiated squamous cell carcinomas did not stain. With prior digestion by neuraminidase, however, positive membrane staining for PNA was demonstrated in the squamous cells of all well-differentiated squamous cell carcinomas and all but one case of the poorly differentiated squamous cell carcinomas. Our results support the efficacy of PNA in most cases as a marker to aid in the often difficult histologic differentiation of keratoacanthoma from well-differentiated squamous cell carcinoma. Our findings also support those of previous authors who suggested that the negative PNA stain of malignant squamous cells is not the result of a lack of PNA receptors, but is due instead to a masking of receptor sites by terminal sialic acid residues.