Human leucocytes (basophils) release histamine when exposed to ragweed antigen E or anti-IgE. The present study shows that when leucocytes from BCG-positive donors are first incubated with PPD and then challenged with anti-IgE, histamine release is enhanced. In contrast, when leucocytes from BCG-negative donors are incubated with PPD and then challenged with anti-IgE there is no enhancement of histamine release. The enhancement of histamine release was detected within 24 hr after addition of PPD, but was maximal at 48 to 72 hr. Supernatant fluids collected from these leucocyte cultures revealed the presence of a soluble mediator(s) which, when incubated with leucocytes from BCG-negative donors, enhanced the release of histamine. Examination of the supernatant fluids from BCG-positive leucocyte cultures stimulated with PPD showed a correlation between histamine-release enhancing activity and interferon. Treatment of the culture fluids at pH 2.0 abolished the anti-viral activity, indicating that the interferon was of the type II or 'immune' class. The same treatment only partly abolished the histamine-release enhancing activity. It is concluded that immune-specific stimulation of leucocytes results in the release of soluble mediators that are capable of enhancing IgE-mediated histamine release.