The speculation that human histamine releasing factor (HRF) - a lymphokine that releases histamine from human tissues, might be the same as gamma-interferon was investigated. The speculation arose from the fact that HRF and gamma-interferons are both lymphokines and have both been reported to affect histamine release from human basophils. Using purified gamma-interferons either naturally obtained or E. coli-derived (recombinant DNA technique), as well as alpha-, alpha-2, arg, and beta-interferons, it was found that: Unlike HRF, the interferons neither induced histamine release nor affected antigen-induced histamine release from human basophils in vitro. HRF is partially acid-stable whereas gamma-interferon is acid labile. HRF samples had little interferon activity which did not correlate with HRF activity. The estimated molecular weight of HRF is 12,000-18,000 daltons and contrasts to those of interferons, which exceed 30,000 daltons. The results strongly suggest that HRF is very unlikely to be a gamma-interferon or indeed any other class of interferon.