Proteinuria plays a pathogenic role in the development of end stage renal disease. Angiotensin converting enzyme (ACE) inhibitors lower proteinuria and are renoprotective. However, large inter-individual variation in antiproteinuric response to ACE inhibitors exists. In this study, we explored the mechanism of therapeutic resistance to an ACE inhibitor in the rat 5/6 nephrectomy model. At week 6 after 5/6 nephrectomy, treatment with lisinopril was initiated for 6 weeks. Proteinuria and blood pressure were evaluated weekly. At the end of the experiment, rats were divided into tertiles according to their antiproteinuric response: (1) responders (n=9), (2) intermediate responders (n=8) and (3) non-responders to ACE inhibitor therapy (n=9). At the start of treatment, proteinuria had progressively increased to 154 (95% confidence interval [CI]: 123-185) mg/24 h in the entire cohort, with comparable proteinuria and blood pressure in all groups. Following treatment with ACE inhibitor, proteinuria was significantly lower in the responders (68, CI: 46-89 mg/24 h) compared to the non-responders (251, CI: 83-420) mg/24 h). Similarly, blood pressure was reduced in the responders, but unaffected in the non-responders. At autopsy, renal ACE activity and renal ACE expression were significantly lower in the responders compared to the non-responders. Although lisinopril intake was comparable in all animals, urinary drug excretion was increased in the non-responders, demonstrating increased drug clearance. Average urinary lisinopril excretion was correlated with antiproteinuric response (R(2)=0.32, P=0.003). In conclusion, both pharmacodynamic and -kinetic factors account for the non-response to lisinopril. Whether these can be overcome simply by increasing drug dosage in non-responders should be investigated.