It has been suggested that patients with recurrent, unexplained anaphylaxis may be more responsive, and patients with systemic mastocytosis, less responsive, to mast cell-derived mediators, including histamine, compared to normal subjects. This would help explain why patients with recurrent, unexplained anaphylaxis have an anaphylactic response and, conversely, why patients with systemic mastocytosis can tolerate high levels of plasma histamine. To test this hypothesis, intradermal titrations (0.02 ml of solution from 1 ng/ml to 2 μg/ml) of histamine and morphine sulfate (MS) (10 ng/ml to 10 μg/ml) were administered to normal volunteers (N = 15), patients with recurrent, unexplained anaphylaxis (N = 10), and patients with systemic mastocytosis (N = 18). Antihistamines were stopped at least 72 hours before the study. Resultant areas of wheal and flare were determined with a computerized morphometric system. Comparison of any two given means at each dose of histamine or morphine with the two-sample Student's t test with Bonferroni inequality demonstrated no significant differences ( p > 0.05) among the three groups. The median amount of MS or histamine required to produce a half-maximal response was compared for equality. None of the differences observed reached statistical significance, in agreement with the similarity of the dose-response curves. An analysis of the correlation between response to MS and to histamine in individual subjects revealed the responses to be significantly correlated in all cases, with the exception of wheal in patients with recurrent, unexplained anaphylaxis. A similar analysis of the correlation between types of response (wheal versus flare) demonstrated a significant correlation only in patients with mastocytosis, suggesting a modification of the apparently indepdendent mechanisms of response observed in normal subjects. Finally, there was no positive correlation between mast cell numbers, plasma histamine levels, and dermal responses to MS or histamine in patients with mastocytosis. Taken together, these results suggest that patients with recurrent, unexplained anaphylaxis are not more sensitive to histamine, and patients with systemic mastocytosis are not less sensitive to histamine, although in the latter case, there is evidence of a change in the normally independent nature of the dermal responses to histamine and MS.