Cyanide is a readily available and potentially lethal substance. Oral exposure can result in larger doses, compared with other routes. Currently, there are no antidotes specific for use in the treatment of oral cyanide poisoning, and studies cannot be done in humans. We report on a new large animal model of oral cyanide toxicity to evaluate potential antidotes. Six female swine (Sus scrofa; weight, 45 to 55 kg) were anesthetized, intubated, and instrumented. Animals received a KCN bolus of either 5 or 8 mg/kg delivered via orogastric tube. Time to apnea was recorded; parameters monitored included heart rate, respiratory rate, blood pressure, pulse oximetry, end-tidal CO2, arterial blood gasses, and lactate concentrations. The Welch t test was used to calculate confidence intervals, mean, and standard deviation, and a Kaplan-Meier survival curve was used to compare survival between the 2 groups. At baseline, all animals in both groups were similar. Animals in the 5-mg/kg group had a more rapid time to apnea (5.1 ± 2.1 min), longer time to death (48.5 ± 38.1 min), and a greater rate of survival than the 8-mg/kg group (apnea, 10.6 ± 10.7 min; death, 26.1 ± 5.8 min). All animals displayed signs of toxicity (acidemia, hyperlactatemia, hypotension, apnea). We here report a large animal (swine) model of oral cyanide poisoning with dose-dependent effects in regard to time to death and survival rate. This model likely will be valuable for the development of medical countermeasures for oral cyanide poisoning.