Background: Marked variability in the amount of histamine released in the first hour of ongoing cutaneous reactions has been noted. This variability occurs even among subjects with similar degrees of skin test reactivity to antigen. Methods: To determine gender effects on mediator release, we retrospectively compared: (1) skin chamber histamine release after a 0 to 1-hour and 1 to 5-hour exposure to antigen; (2) neutrophil accumulation after 5 hours of antigen exposure and skin test reactivity to antigen, histamine, and codeine in 91 male and 60 female subjects. Results: There was no difference in skin test reactivity to antigen, histamine, or codeine between male and female subjects. However, in the group as a whole, male subjects released higher amounts of histamine in the first hour (74 +/- 4 ng/ml) than female subjects (55 +/- 4 ng/ml), (p < 0.01). When subjects were matched for equivalent skin reactivity to antigen, male subjects who were sensitive to 10 PNU/ml and 1 PNU/ml released more histamine (67 +/- 9 ng/ml and 82 +/- 9 ng/ml) than female subjects (51 +/- 7 ng/ml and 55 +/- 7 ng/ml) (p < 0.05 and < 0.01). In the most sensitive subjects, those with skin sensitivity to 0.01 PNU/ml of antigen, there was not a significant difference between the histamine release in the first hour in male (79 +/- 12 ng/ml) or female (69 +/- 9 ng/ml) subjects. No difference was observed between male and female subjects in either neutrophil or histamine accumulation in the 1- to 5-hour period. Conclusions: Since the first hour release of histamine is secondary to mast cell activation and the 1- to 5-hour histamine release is secondary to basophil activation, we conclude that the gender of the subject influences the degree of in vivo antigen-induced histamine release from mast cells.