Background Assessing the risk of serious adverse events (SAEs) during hypertension treatment is important for understanding the benefit-harm trade-offs of lower blood pressure goals. It is unknown whether high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) provide information about SAEs. Methods and Results In SPRINT (Systolic Blood Pressure Intervention Trial), hs-cTnT and NT-proBNP were measured at baseline in 8828 (94.3%) and 8836 (94.4%) participants, respectively. Multivariable Cox proportional hazards models were used to evaluate hs-cTnT and NT-proBNP associations with a composite of SPRINT's SAEs of interest: hypotension, syncope, bradycardia, acute kidney injury, electrolyte abnormalities, and injurious falls. Elevations in hs-cTnT and NT-proBNP were associated with increased composite SAE risk (hazard ratio [HR] per 2-fold higher hs-cTnT: 1.15; 95% CI, 1.06‒1.25; HR per 2-fold higher NT-proBNP: 1.09; 95% CI, 1.05‒1.14). Compared with both hs-cTnT and NT-proBNP in the lower tertiles, both biomarkers in the highest tertile was associated with increased composite SAE risk (HR, 1.56; 95% CI, 1.32‒1.84). Composite SAE risk was higher in the intensive-treatment group than in the standard-treatment group for participants with both biomarkers in the lower tertiles, but similar between treatment groups for participants with both biomarkers in the highest tertile (P for interaction=0.008). Conclusions Elevations in hs-cTnT and NT-proBNP individually and in combination are associated with higher composite SAE risk in SPRINT. The differential impact of blood pressure treatment on SAE risk across combined biomarker categories may have implications for identifying individuals with more favorable benefit-harm profiles for intensive blood pressure lowering.