Previous work has suggested a key role of dendritic cells in antineoplastic immunity. The course of mycosis fungoides and cancers of the lung, colon, thyroid and stomach has been associated with dendritic cell response to the primary tumor. However, this has not been reported for cutaneous or mucosal squamous cell carcinoma (SCC). Thirty-six cases of primary SCC of the lip mucosa or vermillion border, including nine cases with regional metastasis, were studied to investigate the relationship of dendritic cell density with age, tumor grade, mitotic rate, diameter, ulceration, depth of invasion, muscle invasion, tumor-infiltrating lymphocytes (TILs) and metastasis. Dendritic cells were identified using S100 immunohistochemistry, and their peritumor and intratumor density (peri-S100D and intra-S100D) were determined. The mean peri-S100D was 314 +/- 50/mm2. High peri-S100D was associated with lower rate of metastasis (P = 0.03), and no case with peri-S100D > 311/mm2 metastasized. Peri-S100D inversely correlated with depth of invasion (P = 0.04) and ulceration (P = 0.02), and positively associated with TILs (P = 0.02). The mean intra-S100D was 317 +/- 42/mm2. Intra-S100D did not quantitatively correlate with metastasis; however, no metastasis occurred when intra-S100D exceeded 515/mm2. Intra-S100D correlated with brisk TILs (P = 0.04). These results suggest a functional role of dendritic cells in the immune response to SCC. Peri-S100D may be a prognostic indicator.