Background The strength and direction of the associations between inflammation and coagulation biomarkers with kidney disease onset and progression remain unclear, especially in a population-based setting. Study Design Prospective observational study. Setting & Participants 4,966 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with a cystatin C–based estimate of glomerular filtration rate (eGFRcys) >60 mL/min/1.73 m2 and at least one follow-up measurement of kidney function. All participants were free of cardiovascular disease at entry. Predictor We evaluated the associations of C-reactive protein (CRP), interleukin 6 (IL-6), fibrinogen, factor VIII, and d-dimer levels with kidney function decrease. Outcomes & Measurements Kidney function decrease was assessed primarily by repeated measurements of eGFRcys over 5 years. Rapid decrease in kidney function was defined as eGFR decrease >3 mL/min/1.73 m2 per year. Incident low eGFR was defined as the onset of eGFRcys <60 mL/min/1.73 m2 at any follow-up examination and eGFRcys decrease ≥1 mL/min/1.73 m2 per year. Results Mean age was 60 years, 39% were white, 52% were women, and 11% had diabetes. Mean eGFRcys was 96 mL/min/1.73 m2 and 7% had albuminuria. Median follow-up was 4.77 years. Higher factor VIII levels (per 1 standard deviation [SD] of biomarker) had the strongest association with kidney function decrease (β = −0.25; 95% CI, −0.38 to −0.12; P < 0.001), followed by IL-6 (β = −0.16; 95% CI, −0.29 to −0.03; P = 0.01), CRP (β = −0.09; 95% CI, −0.22 to 0.03; P = 0.1), and fibrinogen levels (β = −0.09; 95% CI, −0.22 to 0.04; P = 0.2). Each 1-SD higher concentration of IL-6 (OR, 1.15; 95% CI, 1.07-1.23), factor VIII (OR, 1.11; 95% CI, 1.03-1.18), and CRP (OR, 1.09; 95% CI, 1.02-1.16) at baseline was associated significantly with rapid kidney function decrease. Only IL-6 level was associated significantly with incident low eGFR (OR, 1.09; 95% CI, 1.00-1.19). Limitations Observational study design and absence of measured GFR. Conclusions Inflammation and coagulation biomarkers are associated with decreasing kidney function in ambulatory adults without established cardiovascular disease or chronic kidney disease.