Across two independent NHANES cohorts totalling 30,533 US adults followed for up to 11.4 years, the neutrophil-to-lymphocyte ratio (NLR) was the strongest of three CBC-derived inflammation indices for predicting cardiovascular mortality — yielding a hazard ratio of 1.32 per 1-SD increase (95% CI 1.21–1.44) in the development cohort and 1.35 (1.22–1.49) in validation. Crucially, when NLR and the systemic immune-inflammation index (SII) were modelled together, only NLR retained significance (HR 1.49), confirming that SII — which mathematically incorporates NLR — adds no independent information. The platelet-to-lymphocyte ratio (PLR) was the weakest predictor throughout.
For adults and clinicians, this is both clarifying and sobering. The finding resolves a practical confusion: laboratories and researchers have published hundreds of studies treating NLR, SII, and PLR as distinct biomarkers, yet this large, externally validated analysis shows they are largely redundant, with NLR sufficient. However, even NLR produced only small, inconsistent improvements in discrimination and reclassification when added to models already achieving a C-index above 0.89 — suggesting the clinical uplift beyond standard risk factors is modest at best. NLR remains a zero-cost marker derivable from any routine blood count, making it worth noting in preventive consultations, but it should not displace established tools like the pooled cohort equations. This preprint has not yet been peer-reviewed, and reclassification inconsistency between cohorts warrants caution before clinical adoption.