OBJECTIVES: The aim of this overview of systematic reviews was to synthesize, appraise, and present all systematic review (SR) evidence on the clinical efficacy of glutamine administration to severely ill patients.METHODS: Medline, Scopus, the Cochrane Library, and Prospero were searched up to March 2020. Systematic reviews and meta-analyses of randomized controlled trials published in English, comparing immunomodulating diets-containing exclusively glutamine-with standard diets for critically ill adult patients were selected. Data were collected from each selected systematic review and all available primary studies. The primary outcome was overall mortality; secondary outcomes were rate of infectious complications, hospital and intensive care unit (ICU) length of stay (LOS).RESULTS: Seventeen SRs were eligible for inclusion. Of the SRs, 16 included meta-analyses with moderate degree of overlap (corrected covered area = 10%). These included 117 randomized controlled trials with 9933 patients. Glutamine supplementation was not associated with overall mortality and ICU LOS. However, it may reduce the rate of infectious complications overall (N = 3666, risk ratio, 0.82; 95% confidence interval [CI], 0.73-0.92; I = 33%: low quality of evidence). LOS was limited with the supplementation of glutamine (N = 4353 weighted mean difference, -2.90; 95% CI, -3.66 to -2.15; I = 81%: very low quality of evidence), but this effect was diminished when only studies with low risk for bias were synthesized.CONCLUSION: Glutamine could demonstrate a beneficial role in critical care patients of diminishing the rate of infectious complications and hospital and ICU LOS. However, future studies with better quality would confirm this finding.