Urticaria pigmentosa (UP) is a clinicopathologic term used to describe reddish-brown cutaneous macules and papules, characterized histologically by mast cell infiltration of the papillary and upper reticular dermis and reactive basal hyperpigmentation of the overlying epidermis. Although typically a benign, self-limited disorder of childhood, a significant proportion (up to 30%) of adolescent and adult-onset UP represents cutaneous involvement by underlying systemic mastocytosis (SM). Predicting the course of cutaneous mast cell disease has been limited by a lack of diagnostic and prognostic markers. In patients with SM, neoplastic bone marrow mast cells show aberrant surface expression of CD25. However, whether CD25 expression on cutaneous mast cells is associated with underlying SM is unknown. In this study, we performed a clinicopathologic analysis of 30 adult patients presenting with UP between 1987 and 2007. Cutaneous mast cell infiltration pattern, cytomorphology, density, and CD25 immunoreactivity were correlated with underlying or subsequent SM. On the basis of clinical and pathologic follow-up, 10 of 30 (33%) patients were diagnosed with SM and 20 of 30 (67%) with limited cutaneous mastocytosis (CM). Although cutaneous mast cell density was slightly higher in patients with SM compared to those with limited CM (P=0.047), neither mast cell cytomorphology nor infiltration pattern correlated with underlying systemic disease. However, cutaneous mast cells from all 10 patients with SM (100%) were immunoreactive for CD25, compared to only 5 of 20 (25%) with limited CM (P<0.001). Our findings suggest that immunoreactivity for CD25 in cutaneous mast cells may be useful for stratifying adult patients presenting with UP for additional clinical evaluation.