It has been suggested that patients who present with episodes of unexplained anaphylaxis (UEA) or unexplained flushing (UEF) have systemic mastocytosis (SM), a proposal believed to be supported by the presence of excess mast cell (MC) numbers in the skin of these individuals. To examine this hypothesis, we determined the number and distribution of MCs in the skin of nine normal subjects, nine patients with UEA/UEF, six patients with urticaria pigmentosa (UP), and 14 patients with SM. Skin biopsy specimens of normal subjects contained 38.4 +/- 4 (mean +/- SEM) MCs per square millimeter. Biopsy specimens of patients with UEA/UEF contained 71.8 +/- 13 MCs per square millimeter. Although the numbers were significantly different from numbers in skin of normal subjects (p less than 0.05), similar modest increases in MC numbers are observed in a number of skin conditions. In marked contrast, lesional biopsy specimens of patients with UP contained 596.5 +/- 278 MCs per square millimeter (p less than 0.05, n = 6, compared to MC numbers in the skin of normal subjects), and patients with SM had 720.6 +/- 176 MCs per square millimeter in lesional skin (p less than 0.01, n = 12, compared to normal skin). Patients with UP or SM also had increased MC numbers in nonlesional skin compared to normal skin (168.0 MCs per square millimeter, p less than 0.05, n = 5, and 184.4 MCs per square millimeter, p less than 0.01, n = 10, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)