Human leukocyte and skin mast cell preparations were incubated with morphine sulfate in concentrations ranging from 1.5 × 10−5. M to 4.5 × 10−5M. Skin mast cells also were incubated with oxymorphone and fentanyl in the same concentrations. Human leukocytes did not release histamine in response to any concentration of morphine. In skin mast cells, histamine release by morphine first was detected at 1.5 × 10−4M. Histamine release further increased at 5.0 × 10−4M with no incremental increase at higher concentrations. Oxymorphone and fentanyl failed to release histamine at any concentration. Histamine release by morphine required calcium but was not influenced by changes in the 1–4 nM range. Skin mast cell preparations were pretreated for 30 min in naloxone 5 × 10−4M and then morphine 5 × 10−4M was added for 30 min without removing naloxone. Naloxone neither released histamine nor inhibited morphine-induced histamine release. The release of histamine by morphine but not equimolar concentrations of fentanyl and oxymorphone indicates that histamine release by narcotics is not a nonspecific effect of high drug concentration. The failure of naloxone to inhibit morphine-induced histamine release suggests that histamine release by morphine is not dependent on opiate receptor binding or activation. These results indicate that this human mast cell preparation will be useful in further understanding the mechanism of histamine release induced by morphine and other agents.