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Background: Widow spider-bite causes latrodectism and is associated with significant morbidity worldwide. Antivenom is given by both the intravenous (IV) and intramuscular (IM) routes and it is unclear which is more effective. Aim: To compare the effectiveness of IV vs. IM redback spider antivenom. Design: Randomized controlled trial. Methods: Patients with latrodectism were given either IV or IM antivenom according to a randomized double-dummy, double-blind protocol. The first antivenom treatment was followed by another identical treatment after two hours if required. The primary outcome was a clinically significant reduction in pain two hours after the last treatment. A fully Bayesian analysis was used to estimate the probability of the desired treatment effect, predetermined as an absolute difference of 20%. Results: We randomly allocated 126 patients to receive antivenom IV (64) and IM (62). After antivenom treatment pain improved in 40/64(62%) in the IV group vs. 33/62(53%) in the IM group (+9%; 95% Credible Interval [CrI]: –8% to +26%). The probability of a difference greater than zero (IV superior) was 85% but the probability of a difference >20% was only 10%. In 55 patients with systemic effects, these improved in 58% after IV antivenom vs. 65% after IM antivenom ( 8%; 95% CrI: –32% to +17%). Twenty-four hours after antivenom pain had improved in 84% in the IV group vs. 71% in the IM group (+13%; 95% CrI: –2% to +27%). A meta-analysis including data from a previous trial found no difference in the primary outcome between IV and IM administration. Discussion: The difference between IV and IM routes of administration of widow spider antivenom is, at best, small and does not justify routinely choosing one route over the other. Furthermore, antivenom may provide no benefit over placebo.