Background : Interferon gamma‑1b has been proposed to treat critical illness-induced immunosuppression. We aimed to determine the effects on 90-day outcomes and the cost-effectiveness of interferon gamma‑1b compared to placebo in mechanically ventilated critically ill patients. Methods : A cost-effectiveness analysis (CEA) was embedded in the “PREV-HAP trial”, a multicenter, placebo‑controlled, randomized trial, which randomly assigned critically ill adults under mechanical ventilation to receive interferon gamma or placebo. The CEA compared interferon-gamma with placebo using a collective perspective at a 90-day time horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER) expressed in terms of adjusted cost per adjusted Quality-Adjusted Life-Years (QALYs) gained. QALYs were estimated from the responses of patients and proxy respondents to the health-related quality of life questionnaire EQ-5D-3L. Results : The 109 patients in the PREV-HAP trial were included in the CEA. At day 90, all-cause mortality rates were 23.6% in the interferon group and 25% in the placebo group (Odds Ratio (OR) = 0.88 (0.40 –1.93) p = 0.67). The difference in the mean adjusted costs per patient at 90 days was €-1.638 (95%CI €-17.534 to €11.968) in favor of interferon gamma-1b. The mean difference in adjusted QALYs between interferon gamma-1b and the placebo group was + 0.019 (95%CI -0.005 to 0.043). The probability that interferon gamma-1b was cost-effective ranged from 0.60 to 0.71 for a willingness to pay a QALY between €20k and €150k for the base case analysis. Conclusion : Early administration of interferon gamma might be cost-effective in critically ill patients supporting the realization of other studies on this treatment. However, the generalization of the findings should be considered cautiously, given the small sample size due to the premature end of PREV-HAP. Trial registration ClinicalTrials.gov Identifier: NCT04793568, Registration date: 2021–02-24.