Several studies have now examined the cDNA expression profiles of healthy myometrium, leiomyomas (LM), and leiomyosarcomas (LMS). This has produced a list of candidate genes that might be useful tools for distinguishing these entities from each other. The potential candidates identified from this body of research include insulinlike growth factor 1, h-caldesmon, cytokeratin 18, and the cyclin-dependent kinase 4 inhibitor, p16. To determine whether the immunohistochemical expression of these proteins could aid in the diagnosis of LMS and LM variants, we constructed a tissue microarray consisting of cases of healthy myometrium (n = 10), LM (not otherwise specified and variants; n = 47), and LMS (n = 8), and then measured the immunoreactivity of each of these proteins. The cases were scored on the basis of staining intensity (weak, moderate, or strong) and extent (focal or diffuse) and were assigned a final score from 0 to +3. Immunostaining for p16 was statistically stronger in LMS than in LM and its subtypes (P < 0.001). Specifically, the p16 immunostaining score in LMS cases (n = 8) was at least +2, whereas the p16 immunostaining scores in all LM cases (n = 47) were either 0 (n = 35) or +1 (n = 12). The expression of the remaining antibodies did not show a statistically significant difference between the 2 groups. Furthermore, none of the markers studied showed any differences among the LM variants. The results of this study confirm the overexpression of p16 in LMS and suggest that p16 can serve as a reliable immunohistochemical marker in distinguishing uterine LMS from LM and its benign variants.