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Background. Systemic inflammation is a pathogenic mechanism shared by infection and cancer. Mortality from Covid-19 is strongly linked to systemic cytokine excess. We investigated systemic inflammation as a driver of Covid-19 severity in patients with Covid-19 and cancer. Methods. Between 27/02 and 23/06/2020, OnCovid retrospectively accrued 1,318 consecutive European cancer patients with Covid-19. Patients with myeloma, leukemia, or insufficient data were excluded. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and prognostic index (PI) were evaluated for their prognostic potential, with the NLR, PLR, and PNI risk stratifications dichotomized around median values, and the pre-established risk categorizations from literature utilized for the mGPS and PI. Results. 1,071 eligible patients were randomly assorted into a training set (TS, n=529) and validation set (VS, n=542) matched for age (67.9±13.3 TS, 68.5±13.5 VS), presence of >1 comorbidity (52.1% TS, 49.8% VS), development of >1 Covid-19 complication (27% TS, 25.9% VS), and active malignancy at Covid-19 diagnosis (66.7% TS, 61.6% VS). Among all 1,071 patients, deceased patients tended to categorize into poor risk groups for the NLR, PNI, mGPS, and PI (P6 (44.6% vs 28%, P6 30 days 95%CI 1-63, PNI Conclusion. Systemic inflammation drives mortality from Covid-19. Hypoalbuminemia and lymphocytopenia as measured by the PNI are the most accurate predictors of outcome and enable repurposing of the PNI as the OnCovid Inflammatory Score (OIS) as a readily available biomarker of severity. Citation Format: Gino M. Dettorre, Saoirse Dolly, Angela Loizidou, John Chester, Amanda Jackson, Uma Mukherjee, Alberto Zambelli, Juan Aguilar-Company, Mark Bower, Christopher C. Sng, Ramon Salazar, Alexia Bertuzzi, Joan Brunet, Ricard Mesia, Ailsa Sita-Lumsden, Elia Seguí, Federica Biello, Daniele Generali, Salvatore Grisanti, Pavetha Seeva, Gianpiero Rizzo, Michela Libertini, Antonio Maconi, Charlotte Moss, Josep Tabernero, Beth Russell, Nadia Harbeck, Bruno Vincenzi, Rossella Bertulli, Diego Ottaviani, Raquel Liñan, Andrea Marrari, M. Carmen Carmona-García, Neha Chopra, Carlo Tondini, Oriol Mirallas, Valeria Tovazzi, Vittoria Fotia, Claudia Andrea Cruz, Nadia Saoudi-Gonzalez, Eudald Felip, Ariadna Roqué, Alvin J. Lee, Thomas Newsom-Davis, Andrea Patriarca, Lorenza Rimassa, Armando Santoro, Alessandra Gennari, Nikolaos Diamantis, David J. Pinato. The acute phase response identifies cancer patients with adverse outcomes from SARS-CoV-2 infection as quantified by the OnCovid Inflammatory Score [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 701.