Background and aimThe Naples prognostic score (NPS) is a recognized inflammatory and nutritional scoring system used as a prognostic indicator in various cancers and, more recently, in non-cancer diseases. Its association with mortality in individuals with Metabolic Syndrome (MetS) is understudied. This study aims to investigate the link between NPS and both all-cause and cardiovascular disease (CVD) mortality in adults with MetS. Methods and resultsThis study included individuals with MetS from the National Health and Nutrition Examination Survey (NHANES) 1999-2016. Mortality data were linked to National Death Index records up to December 31, 2019. MetS was defined using NCEP ATP III criteria. NPS was calculated using serum albumin, total cholesterol, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio, classifying participants into three groups. Survival differences were assessed using Kaplan-Meier analysis and Log-rank tests. Cox proportional hazards regression determined hazard ratios (HR) with 95% confidence intervals (CI). The study included 13,757 participants, with 2,744 (19.95%) in the low group, 9,140 (66.44%) in the medium group, and 1,873 (13.61%) in the high group. Over a median follow-up of 9.16 years, there were 3,292 all-cause deaths and 1,136 cardiovascular deaths. Compared to the low group, the high group had adjusted HRs of 1.74 (95% CI: 1.51, 2.01) for all-cause mortality and 1.60 (95% CI: 1.25, 2.04) for cardiovascular mortality (all P for trend < 0.01). ConclusionsNPS is a significant prognostic indicator for both all-cause and cardiovascular mortality in individuals with MetS, showing a positive correlation with mortality risk, reinforcing its potential clinical utility.