Background: Insulin resistance is an integral component of a multi-organ dysfunction syndrome (MODS) associated with increased mortality. We determined a cutoff value for the homeostatic model assessment of insulin resistance (HOMA-IR) during an ICU admission that could predict 28-day mortality of nondiabetic MODS patients. Materials and methods: In this prospective, outcome assessor blinded cohort design, we evaluated 82 such patients for fasting blood glucose (FBG)/insulin levels (FIL) during an ICU admission and followed their outcome for 28 days. The primary outcome variable was the HOMA-IR score calculated from the above variables. The statistical tool included receiver operating characteristic curve, Youden index, and correlation and regression analysis. Results: Overall, 38 patients succumbed to their illness. The optimal cutoff value for HOMA-IR was ≥1.61 (area under curve: 0.684, sensitivity: 36.8%, specificity: 95.5%). The 28-day survival was significantly lower (p = 0.001) at HOMA-IR threshold ≥1.61 (odds ratio: 12.25, hazard ratio: 2.98). The mean HOMA-IR among survivors vs nonsurvivors was 0.76 ± 0.61 and 1.38 ± 1.14, respectively (p = 0.004). Except for FIL and FBG, HOMA-IR values did not correlate with any other baseline or outcome parameters (demographics, APACHE II/sequential organ failure assessment score, vasopressor needs, or ICU/hospital stay). On comparing these parameters across the HOMA-IR threshold, only FIL and the hospital stay varied significantly. Most of the outcome parameters, however, varied significantly among nonsurvivors vs survivors. Conclusion: The HOMA-IR is a significant predictor of mortality in MODS. Its cutoff value may assist in determining a reference range for critically ill patients. Its routine use in the light of other disease severity scores may serve in their better prognostication.