Abstract Blood pressure reduction and angiotensin-converting enzyme (ACE) inhibitors slow but do not stop progressive decline of renal function in established diabetic nephropathy (DN), but predictors of this decline in patients undergoing these interventions are unknown. We prospectively examined patients to determine whether age, sex, ethnicity, mean blood pressure, plasma creatinine, urine protein excretion, and cigarette smoking predict renal function decline in type 2 DN treated toward the recommended mean blood pressure goal of 92 mm Hg (about 125/75 mm Hg) with antihypertensives including ACE inhibitors. Thirty-three DN patients with initial plasma creatinine less than 1.4 mg/dL were followed 64.0 ± 1.1 months. After correcting for differences in follow-up time, demographic variables, and other relevant variables, plasma creatinine increased, indicating renal function decline despite mean blood pressure reduction to 92 ± 1 mm Hg and administration of ACE inhibitors. Regression analysis showed that smoking was the only examined parameter that significantly predicted renal function decline. Smokers (n = 13) and nonsmokers (n = 20) had similar follow-up (61.4 ± 2.1 months versus 65.7 ± 1.1 months), mean blood pressure (91 ± 1 mm Hg versus 92 ± 1 mm Hg), and initial plasma creatinine (1.05 ± 0.08 mg/dL versus 1.08 ± 0.03 mg/dL). Nevertheless, follow-up plasma creatinine was higher in smokers than nonsmokers (1.78 ± 0.20 mg/dL versus 1.32 ± 0.04 mg/dL). The data show that renal function declines faster in smokers than nonsmokers with type 2 DN undergoing treatment to improve blood pressure including ACE inhibitors. Cigarette smoking remains a risk factor for renal function decline in type 2 DN despite currently recommended therapy. © 2002 by the National Kidney Foundation, Inc.