Background Neprilysin is a metalloprotease involved in proteolysis of numerous peptides, including natriuretic peptides, and is of prognostic and therapeutic importance in heart failure with reduced ejection fraction. No studies have investigated circulating neprilysin in the community, its clinical correlates, or its relationship to cardiovascular disease in the general population. Methods and Results Plasma neprilysin was measured in 1536 participants from Olmsted County, Minnesota, using a commercially available sandwich ELISA assay. Clinical and echocardiographic correlates and subsequent outcomes were determined. Soluble neprilysin is non‐normally distributed in the community (median: 3.9 ng/mL; interquartile range: 1.0–43.0 ng/mL). There was no relationship between plasma neprilysin and age (Spearman correlation: −0.04, P=0.16); body mass index (Spearman correlation: −0.04, P=0.16); glomerular filtration rate (Spearman correlation: −0.007, P=0.8); or A‐, B‐, or C‐type natriuretic peptides (Spearman correlation: 0.03, P=0.22; −0.001, P=0.96; 0.01, P=0.67, respectively). Among tertiles of neprilysin, the lowest tertile group had the highest prevalence of smokers (P