Background Experimental studies show that high-sodium intake affects the innate immune system, among others with increased circulating granulocytes. Whether this relationship exists on a population level and whether this relates to disease outcomes is unclear. We aimed to test the hypotheses that (1) sodium intake is associated with granulocytes on a population level; (2) granulocytes are associated with the presence of hypertension and both cardiovascular and renal outcomes; and (3) the relation between high-sodium intake and these outcomes is mediated by granulocytes. Methods and Results We performed an analysis in 13 804 participants from the prospective EPIC (European Prospective Investigation into Cancer)-Norfolk cohort, with a mean age of 58 years and median follow-up of 19.3 years. Analyses were carried out using calculated estimated sodium intake and sodium-to-potassium ratios from spot urines at baseline. The main outcomes were hypertension at baseline, and composite cardiovascular (mortality or cardiovascular events) and renal (mortality or renal events) outcomes during follow-up. Sodium intake and urine sodium-to-potassium ratio were positively associated with circulating granulocyte concentrations after adjustment for confounders (β=0.03; P=0.028 and β=0.06; P<0.001, respectively). Granulocytes significantly mediated the associations of, respectively, sodium intake and urine sodium-to-potassium ratio with hypertension at baseline, and cardiovascular and renal outcomes. Conclusions Sodium intake is positively associated with circulating granulocyte concentrations, and higher granulocyte concentrations associate with worse long-term cardiovascular and renal outcomes. Given the recently established immune-modulating effects of sodium and the role of immune cells in both cardiovascular and renal disease, causality for this pathway may need consideration in further studies.