Mortality remains elevated during venoarterial extracorporeal membrane oxygenation support (VA-ECMO) for cardiogenic shock and the role of inflammation is uncertain. By using the neutrophil-to-lymphocyte ratio (NLR), we investigated inflammatory dynamics during VA-ECMO and their relation to clinical outcomes. A single-center, retrospective cohort study was conducted. Patients receiving steroids or on-device support for less than 48 hours were excluded. Patients were grouped as those who did and did not have a persistent rise in NLR during the 24–48 hour interval after VA-ECMO placement. Overall, 253 patients comprised the study cohort. In-hospital mortality was 56%. Neutrophil-to-lymphocyte ratio was higher at 24 hours after VA-ECMO placement compared to pre-ECMO (Δ4.36, interquartile range [IQR]: −0.23 to 8.61, p < 0.001). Persistent increase in NLR during the 24–48 hour interval after VA-ECMO placement was associated with higher in-hospital mortality (adjusted hazard ratio [aHR]: 1.51, 95% confidence interval [CI]: 1.02–2.25, p = 0.04). The magnitude of this rise in NLR was incrementally related to greater in-hospital mortality (Δ0–5: 72%, aHR: 1.61, 95% CI: 1.03–2.54, p = 0.039; Δ>5: 79%, aHR: 1.64, 95% CI: 1.03–2.63, p = 0.037) in comparison 52%, for those with a drop in NLR. Venoarterial extracorporeal membrane oxygenation exacerbates inflammation, as evident by a rise in NLR, which is progressively higher in nonsurvivors.