Atherosclerotic cardiovascular disease (CVD) is the major cause of death in patients with type 1 diabetes mellitus (T1DM). Alterations in the HDL proteome associate with prevalent CVD in T1DM. We therefore determined which proteins carried by HDL might predict incident CVD in T1DM patients. Using targeted MS/MS, we quantified 50 proteins in HDL from 181 T1DM subjects enrolled in the prospective Coronary Artery Calcification in Type 1 Diabetes study (CACTI). We used Cox proportional regression analysis and a case-cohort design to test associations of HDL proteins with incident CVD (myocardial infarction, coronary artery bypass grafting, angioplasty, or death from coronary heart disease). Only one HDL protein—SFTPB (pulmonary surfactant protein B)—predicted incident CVD in all of the models tested. In a fully adjusted model that controlled for lipids and other risk factors, the hazard ratio was 2.17 per SD increase of SFTPB (95% confidence interval, 1.12-4.21, P=0.022). Plasma fractionation demonstrated that plasma SFTPB is nearly quantitatively bound to HDL. Although previous studies have shown that high plasma levels of SFTPB associate with prevalent atherosclerosis only in smokers, we found that SFTPB predicted incident CVD in T1DM independently of smoking status. Elevated levels of SFTPB in HDL strongly predicted incident CVD in CACTI subjects independently of a wide range of confounding factors, including smoking status, HDL-C, LDL-C, and triglyceride levels. Because SFTPB is almost quantitatively bound to plasma HDL, our observations support the proposal that SFTPB carried by HDL is a marker—and perhaps mediator—of CVD risk in patients with T1DM.