This investigation was carried out to study allergic contraction of passively sensitized human airway smooth muscle in response to specific antigen challenge. We attempted to determine the role played by histamine, slow reaction substances (SRSs), and cyclooxygenase products in the mediation of this response in tracheal smooth muscle. Tissues were passively sensitized with serum from ragweed-sensitive patients (15 h, 4 °C). Subsequent challenge with ragweed antigen produced a slowly developing contraction. The peak contraction to a dose producing a maximal response was 37 ± 6% of the carbachol maximum. Mepyramine (5 × 10−6 M) did not alter the contraction. Methylprednisolone (2 × 10−5 M) attenuated the response to antigen but had no significant effect on the contractile response to arachidonic acid. Indomethacin (5.6–28 × 10−6 M) enhanced the peak antigen-induced contractions by 25 ± 11% whereas 5, 8, 11, 14-eicosatetraynoic acid (6.4 × 10−5 M) selectively attenuated the antigen-induced contraction by 86 ± 12%. Nordihydroguarietic acid (6–12 × 10−6 M) attenuated both the antigen plus arachidonate induced responses. FPL-55712 (1–2 × 10−6 M) antagonized the contractions to antigen. Compound 48/80 and goat antihuman immunoglobulin E produced similar slowly developing contractions in sensitized and in some nonsensitized tissues. These responses, except for an early component of the response to 48/80, were independent of histamine and were reversed by FPL-55712. These findings suggest that arachidonic acid metabolites mediate (slow reacting substances) and modulate (prostaglandins) allergic contraction of human airway smooth muscle while any histamine released contributes little or nothing to the contraction in the larger airways.