Post-cardiotomy vasoplegia syndrome (VS) is often linked to an exaggerated inflammatory response to cardiopulmonary bypass (CPB). At the same time, the prognostic role of platelet-leucocyte indices (PLIs) and leucocyte indices (LIs), (platelet-lymphocyte ratio [PLR], systemic immune-inflammation index [SII = platelet × neutrophil/lymphocyte], aggregate index of systemic inflammation [AISI = platelet × monocyte × neutrophil/lymphocyte], and neutrophil-lymphocyte ratio [NLR], systemic inflammation response index [SIRI = monocyte × neutrophil/lymphocyte), respectively] has been recently described in diverse inflammatory settings. The retrospective study was conducted to evaluate the VS predictive performance of PLIs and LIs in 1,045 adult patients undergoing elective cardiac surgery at a tertiary care center. VS was defined by mean blood pressure <60 mmHg, low systemic vascular resistance (SVRI <1,500 dynes.s/cm 5/m2), a normal or high CI (>2.5 L/min/m2), and a normal or reduced central filling pressure despite high-dose vasopressors. About 205 (19.61%) patients developed VS postoperatively. On univariate analysis, age, diabetes, dialysis-dependent renal failure, preoperative congestive heart failure (CHF), the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II, ejection fraction, NLR, PLR, SII, SIRI, AISI, CPB, and aortic cross clamp (ACC) duration, packed red blood cell (PRBC) transfusion, and time-weighted average blood glucose predicted VS. Subsequent to the multivariate analysis, the predictive performance of EuroSCORE II (OR: 3.236; 95% CI: 2.345-4.468; P < 0.001), CHF (OR: 1.04; 95% CI: 1.02-1.06; P = 0.011), SII (OR: 1.09; 95% CI: 1.02-1.18; P = 0.001), AISI (OR: 1.11; 95% CI: 1.05-1.17; P < 0.001), PRBC (OR: 4.747; 95% CI: 2.443-9.223; P < 0.001), ACC time (OR: 1.003; 95% CI: 1.001-1.005; P = 0.004), and CPB time (OR: 1.016; 95% CI: 1.004-1.028; P = 0.001) remained significant. VS predictive cut-offs of SII and AISI were 1,045 1045×109 /mm3 and 137532×109/mm3, respectively. AISI positively correlated with the postoperative vasoactive-inotropic score (R = 0.718), lactate (R = 0.655), mechanical ventilation duration (R = 0.837), and ICU stay (R = 0.757). Preoperative elevated SII and AISI emerged as independent predictors of post-cardiotomy VS.