Introduction <p>Cyanide poisoning poses an ongoing threat to military personnel and civilian populations. FDA approved antidotes require intravenous administration which can be challenging to accomplish in austere environments. Intranasal (IN) delivery is an innovative approach to developing easy to administer medical countermeasures for field use. Rapid absorption through the nasal mucosa and passage of dimethyl trisulfide across the blood-brain barrier could enhance effectiveness in mitigating cyanide toxicity.</p> Methods <p>An acutely lethal swine model of cyanide poisoning was used to assess the efficacy of IN dimethyl trisulfide (DMTS) on survival, clinical outcomes, and cognitive function. Swine were anesthetized and instrumented for monitoring of vital signs and blood sampling prior to exposure to potassium cyanide. Cyanide exposure continued until 6&#xa0;min after apnea occurred. Upon cessation of cyanide exposure IN DMTS (<i>n</i> = 12) or saline control (<i>n</i> = 6) was administered. Six animals from the DMTS treatment group were survived for 7 days post treatment to assess for cognitive deficits following rescue.</p> Results <p>Prior to experimentation physiological and laboratory characteristics were similar across both study groups. Following treatment, survival in the DMTS group was 75% compared to 0% in the control group (<i>p</i> = 0.0014). Blood lactate concentration in the DMTS group was significantly improved (i.e., lower) compared to controls (<i>p</i> &lt; 0.0001; 6.78 ± 4.58 vs. 17.22 ± 2.56 mmol/L, respectively). Additionally, swine treated with IN DMTS demonstrated no long-term cognitive deficits 7 days post rescue.</p> Conclusion <p>Treatment with IN DMTS improved survival and clinical outcomes in an acutely lethal porcine model of cyanide poisoning.</p>