Background: Non-hepatic hyperammonemia can damage the central nervous system (CNS) and possible prognostic factors are lacking. This study aimed to investigate the prognostic and risk factors for patients admitted to the intensive care unit (ICU).Methods: This prospective, observational, multicenter study was conducted between November and December 2019 at 11 ICUs in the Chinese Heilongjiang province. Changes in blood ammonia level during and after ICU admission were continuously monitored, expressed as the high-level (H-), mean-level (M-), and initial-level (I-) of ammonia. The risk factors of poor prognosis were investigated by conducting univariate and multivariate logistic regression analyses. Receiver operating characteristic curve (ROC) analysis was conducted to compare predictive ability of APACHE-II score, lactic acid, TBil, M-ammonia.Results: A total of 1060 patients were included in this study, of which 707 (67%) had a favorable prognosis and 353 (33%) had a poor prognosis. As shown by univariate models, a poor prognosis was associated with elevated serum levels of lactic acid, TBil, and ammonia (P<0.05), and pathologic scores from three assessments: APACHE-II, GCS, and SOFA. Multivariate analysis revealed that circulating mean ammonia levels in ICU patients were independently associated with a poor prognosis (OR=1.73, 95% CI: 1.07-2.80, P=0.02). However, the APACHE-II score (AUC: 0.714, sensitivity: 0.86, specificity: 0.68, P <0.001) remained the most predictive factor for patient prognosis by ROC analysis.Conclusions: Elevated serum levels of ammonia in the blood were independently prognostic for ICU patients without liver disease.Trial registration: ChiCTR1900026632. Registered 16 October 2014.