Lowering blood pressure (BP) can lead to an initial decline in estimated glomerular filtration rate (eGFR). However, there is debate how much eGFR decline is acceptable. We performed a post hoc analysis of ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure) and SPRINT (Systolic Blood Pressure Intervention Trial), which randomized patients to intensive or standard systolic BP-targets. We determined the relation between initial decline in mean arterial pressure and eGFR. Subsequently, we stratified patients to BP-target and initial eGFR decrease and assessed the relation with annual eGFR decline after 1 year. A total of 13 266 patients with 41 126 eGFR measurements were analyzed. Up to 10 mm Hg of BP-lowering, eGFR did not change. Hereafter, there was a linear decrease of 3.4% eGFR (95% CI, 2.9%–3.9%) per 10 mm Hg mean arterial pressure decrease. The observed eGFR decline based on 95% of the subjects varied from 26% after 0 mm Hg to 46% with a 40 mm Hg mean arterial pressure decrease. There was no difference in eGFR slope ( P =0.37) according to initial eGFR decline and BP-target, with a decrease of 1.24 (95% CI, 1.09–1.39), 1.20 (95% CI, 0.97–1.43), and 1.14 (95% CI, 0.77–1.50) in the 5%, 5% to 20%, and >20% stratum during intensive and 0.95 (95% CI, 0.81–1.09), 1.23 (95% CI, 0.97–1.49), and 1.17 (95% CI, 0.65–1.69) mL/minute per 1.73 m ² per year during standard treatment. In patients at high cardiovascular risk with and without diabetes mellitus, we found no association between initial eGFR and annual eGFR decline during BP-lowering treatment. Our results support that an eGFR decrease up to 20% after BP lowering can be accepted and suggest that the limit can be extended up to 46% depending on the achieved BP reduction. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00000620, NCT01206062.