Coronary artery disease (CAD) and peripheral artery disease (PAD) are common and dangerous conditions that are both driven by atherosclerosis. Despite sharing many major risk factors, their disease pathophysiology is not fully understood. In this study, we aimed to better distinguish common vs. unique biological pathways underlying CAD and PAD by proteomics profiling plasma samples from a subset of participants in the Project Baseline Health Study (PBHS). We identified 14 proteins associated with coronary artery calcium (CAC) score ≥100 and 39 proteins associated with the ankle brachial index (ABI) after covariate adjustment. Two proteins (complement component 7 [C7] and polymeric immunoglobulin receptor [PIGR]) were significantly associated with both CAC and ABI. Our work highlights the potential molecular pathways unique to these diseases, which could have therapeutic implications for personalizing clinical management.