Keratoacanthoma (KA) is a fairly common neoplasm that in the past has been considered by many to be benign. Keratoacanthoma is usually differentiated from squamous cell carcinoma (SCC) by histopathologic criteria. However, the cytologic features of KA and SCC are often similar. Hence, KA may be confused with SCC at the histopathologic level. Volume-weighted mean nuclear volume (Vv) is determined by a technique that permits an unbiased and efficient estimation of nuclear volumes in tissues without any assumptions regarding nuclear shape. In this study, the volume-weighted mean nuclear volume was determined in 18 KAs and 19 SCCs to investigate whether this stereologic approach may be of use in the differentiation of these two tumors. Vv was determined by computer-assisted image analysis (IBAS 20, Kontron, Germany) on Feulgen-stained sections employing stereologic estimation of the volume-weighted mean nuclear volume. The mean Vv of KA was 704.5 microm3 (SD +/-170.5), whereas SCC exhibited a significantly lower Vv of 533.9 microm3 (SD+/-164.9) (p = 0.006). The sensitivity and specificity of Vv for the discrimination between KA and SCC was 0.80 and 0.78, respectively. We found that KAs show a significantly larger Vv than SCCs and thus, the estimation of the volume-weighted mean nuclear volume may be regarded as a helpful tool for the differential diagnosis of KA and SCC.