Background: Sickle cell trait affects ∼ 8% of African American individuals, along with many other individuals with ancestry from malaria-endemic regions worldwide. While traditionally considered a benign condition, recent evidence suggests sickle cell trait is associated with lower eGFR and higher risk of kidney diseases, including end-stage kidney disease. The mechanisms underlying these associations remain poorly understood. We utilized proteomic profiling to gain insight into the pathobiology of sickle cell trait. Methods: We measured proteomics (N=1,285 proteins assayed by Olink Explore) using baseline plasma samples from 592 African American participants with sickle cell trait and 1:1 age-matched African American participants without sickle cell trait from the prospective Women’s Health Initiative (WHI) cohort. Age-adjusted linear regression was used to assess the association between protein levels and sickle cell trait. Results: In age-adjusted models, 35 proteins were significantly associated with sickle cell trait after correction for multiple testing. Several of the sickle cell trait-protein associations were replicated in two independent cohorts of African American individuals (Atherosclerosis Risk in Communities study and Jackson Heart Study) assayed using an orthogonal aptamer-based proteomic platform (SomaScan). Many of the validated sickle cell trait-associated proteins are either known biomarkers of kidney function or injury (e.g., KIM-1, UMOD, ephrins), related to red cell physiology or hemolysis (EPO, HMOX1, AHSP), and/or inflammation (fractalkine, MCP-1, UPAR). A protein risk score constructed from the top sickle cell trait-associated biomarkers was associated with incident kidney failure among those with sickle cell trait during WHI follow-up (odds ratio 1.32; 95%CI 1.10 - 1.58). Conclusions: We identified and replicated the association of sickle cell trait with a number of plasma proteins related to hemolysis, kidney injury, and inflammation.