Objective: We examined the relationship of inflammatory and endothelial dysfunction markers with the prevalence and incidence of gross proteinuria (GP) in persons with type 1 diabetes mellitus. Design: A longitudinal population-based cohort of persons with type 1 diabetes mellitus was followed from 1990-1992 through 2005-2007. Methods: Prevalence and 15-year cumulative incidence of GP were defined as outcome variables. Serum high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), soluble vascular cell adhesion molecule-1 (VCAM-1), soluble intercellular adhesion molecule-1, and serum total homocysteine were measured. Multivariate logistic and discrete linear logistic regression modeling was used for data analysis. Results: After controlling for duration of diabetes and other confounding factors, TNF-α (odds ratio (OR) 3.64; 95% confidence interval (CI) 2.33, 5.70), IL-6 (OR 1.41; 95% CI 1.06, 1.88), VCAM-1 (OR 13.35; 95% CI 5.39, 33.07), and homocysteine (OR 2.98; 95% CI 1.73, 5.16) were associated with prevalent proteinuria. Only hsCRP (OR 1.47; 95% CI 1.02, 2.11) was associated with incident proteinuria. Conclusions: These findings suggest a role of inflammation and endothelial dysfunction as markers and contributors of the development of diabetic nephropathy in persons with type 1 diabetes mellitus.