In this post hoc, secondary analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, an angiotensin-converting enzyme (ACE) inhibition risk/benefit profile was assessed in 322 patients with nondiabetic, proteinuric chronic nephropathies and different degrees of renal insufficiency. The rate of GFR decline (Delta GFR) and the incidence of end-stage renal disease (ESRD) during ramipril or non-ACE inhibitor treatment were compared within three tertiles of basal GFR. Delta GFR was comparable in the three tertiles, whereas the incidence of ESRD was higher in the lowest tertile than in the middle and highest tertiles. Ramipril decreased Delta GFR by 22%, 22%, and 35% and the incidence of ESRD by 33% (P < 0.05), 37%, and 100% (P < 0.01) in the lowest, middle, and highest tertiles, respectively. Delta GFR reduction was predicted by basal systolic (P < 0.0001), diastolic (P = 0.02), and mean (P < 0.001) BP and proteinuria (P < 0.0001) but not by basal GFR (P = 0.12). ESRD risk reduction was predicted by basal proteinuria (P < 0.01) and GFR (P < 0.0001) and was strongly dependent on treatment duration (P < 0.0001). Adverse events were comparable among the three tertiles and within each tertile in the two treatment groups. Thus, disease progression and response to ACE inhibition do not depend on severity of renal insufficiency. The risk of ESRD and the absolute number of events saved by ACE inhibition is highest in patients with the lowest GFR. However, renoprotection is maximized when ACE inhibition is started earlier and when long-lasting treatment may result in GFR stabilization and definitive prevention of ESRD.