Lowering blood pressure may affect renal function. Current guidelines state that reducing antihypertensive therapy should be considered in patients with a >30% serum creatinine increase after initiation of antihypertensive therapy. We examined the association between a serum creatinine increase and adverse clinical outcomes in the ACCORD-BP trial (Action to Control Cardiovascular Risk in Diabetes Blood Pressure), were patients with type 2 diabetes mellitus were randomized to intensive (target systolic blood pressure <120 mm Hg) and standard antihypertensive (<140 mm Hg) treatment. The primary outcome was a combined end point consisting of all-cause mortality, major cardiovascular events, and renal failure. Patients were stratified into 3 groups according to serum creatinine increase between baseline and 4 months (<10%, 10%–30%, >30%). A total of 4733 patients, aged 62.2 years, 52% men with a mean estimated glomerular filtration rate 81.5 mL/min per 1.73 m ² were included. Follow-up was available for 4446 patients, 2231 were randomized to intensive and 2215 to standard therapy. Kaplan-Meier analysis showed no association between a serum creatinine increase and the composite end point in the intensive ( P =0.20) and the standard treatment group ( P =0.17). After adjusting for possible confounders, a >30% serum creatinine increase was associated with a higher risk of clinical adverse outcomes in both treatment groups, but to a similar extent. These data suggest that a >30% serum creatinine increase that coincides with lower blood pressure values should not directly lead to a reduction in antihypertensive medication in patients with type 2 diabetes mellitus. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00000620.