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To assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was survival at day 28.Multiple-center, randomized, two-stage, double-blind, placebo-controlled, safety and efficacy study.A total of 124 intensive care units in Europe, North America, South America, South Africa, and Australasia.A total of 797 patients with septic shock diagnosed for <24 hrs.Patients with septic shock were allocated to receive 546C88 or placebo (5% dextrose) for up to 7 days (stage 1) or 14 days (stage 2) in addition to conventional therapy. Study drug was initiated at 0.05 mL·kg−1·hr−1 (2.5 mg·kg−1·hr−1 546C88) and titrated up to a maximum rate of 0.4 mL·kg−1·hr−1 to maintain mean arterial pressure between 70 and 90 mm Hg while attempting to withdraw concurrent vasopressors.Hemodynamic variables, organ function data, microbiological data, concomitant therapy, and adverse event data were recorded at baseline, throughout treatment, and at follow-up. The primary end point was day-28 survival. The trial was stopped early after review by the independent data safety monitoring board. Day-28 mortality was 59% (259/439) in the 546C88 group and 49% (174/358) in the placebo group (p < .001). The overall incidence of adverse events was similar in both groups, although a higher proportion of the events was considered possibly attributable to study drug in the 546C88 group. Most of the events accounting for the disparity between the groups were associated with the cardiovascular system (e.g., decreased cardiac output, pulmonary hypertension, systemic arterial hypertension, heart failure). The causes of death in the study were consistent with those expected in patients with septic shock, although there was a higher proportion of cardiovascular deaths and a lower incidence of deaths caused by multiple organ failure in the 546C88 group.In this study, the nonselective nitric oxide synthase inhibitor 546C88 increased mortality in patients with septic shock.