A monoclonal antibody to recombinant murine tumor necrosis factor-α (TNFα), TN3-19.12, was used to explore pathogenetic mechanisms and therapeutic strategies in gram-negative shock. In mice receiving an LD90 dose of Escherichia coli 0111, TN3-19.12 prevented death if given 1.5 h before or 30 min after challenge. Less protection was conferred if the antibody was given 2.5 h after challenge. In control mice receiving an irrelevant antibody, L2-3D9, TNFα levels rose (⩽185.1 ° 26.1 ng/mI) by 90 min and had returned to baseline by 5 h. Mice receiving TN3-19.12 did not have this response. TN3-19.12 was oflimited benefit in mice receiving Pseudomonas aeroginosa but had no protective effect in cyclophosphamide-treated mice receiving Klebsiella pneumoniae. In L2-3D9-treated mice, TNFα levels were elevated to 61.8 ° 27.9 and 49.7 ° 5.1 ng/mi by 90 min in the two models, respectively. TNFα levels in TN3-19.12-treated mice in these two models were very low (3.9–5.5 ng/mI). TNFα is a mediator in gram-negative shock; antibody to TNFα can be ofvalue in prophylaxis and treatment, but its clinical use remains to be established.