A subplantar injection of 5--100 micrograms adriamycin in the mouse hind paw produced a biphasic inflammatory response. The first phase peaked at 2 h while the second, more severe phase peaked at four to five days. The magnitude of inflammation was dose related. Administration of [EH]adriamycin revealed that 78% of the drug was lost from the paw within one day. The loss of the remaining drug followed a biphasic decay curve. The first-phase half-life was 1.2 days, and the second-phase half-life was 16.0 days. Vascular permeability, as measured by the leakage of intravenously administered [125I]albumin, was increased between day 4 and day 8. Pathologically, the paw had mild edema and hemorrhage by 4 h after adriamycin injection. The most severe pathological response was seen at 5 days with diffuse inflammation characterized by edema of the dermis, cellular debris, and mononuclear inflammatory cells. By 10 days the inflammatory response was still present but the edema was milder. The antihistamine diphenhydramine, an H1-blocker, inhibited the first phase of inflammation at the highest dose tested but had no effect on the second phase of inflammation. The antihistamine metiamide, an H2-blocker; the antiserotonin drug, p-chlorophenylalanine; and the antiinflammatory drugs, aspirin, hydrocortisone, and ibuprofen failed to antagonize adriamycin-induced inflammation at 2 h or 5 days after adriamycin injection. Indomethacin reduced the inflammation after 5 days but only at toxic dose levels.