We examined the role of mast cell infiltrates and other clinical and histological factors in the prognosis of Merkel cell carcinoma. Mast cells were stained immunohistochemically in 36 Merkel cell carcinomas with an antibody to tryptase. The number of stainable cells was quantified within the tumors and surrounding stroma. Other clinical and histological parameters were examined, statistically analyzed, and compared to subsequent clinical course and prognosis. Patient prognosis was worse with higher tumor mast cell numbers (P < 0.002). Prognosis was also found to be adversely affected by the presence of lymphovascular invasion (P = 0.03) and increased tumor size (P = 0.05). Increased mast cells counts, tumor size, and lymphovascular invasion are associated with an adverse prognosis in Merkel cell carcinomas. Evaluation of mast cell infiltrates may provide useful prognostic data and ultimately could assist in selecting patients that require adjuvant treatment in this aggressive form of skin cancer.