Accurate estimates of the outflow resistance of the human cerebrospinal fluid system are important for the diagnosis of a medical condition known as hydrocephalus. In this paper we design a nonlinear observer which provides on-line estimates of the outflow resistance, to the best of our knowledge the first method to do so. The output of the observer is proven to globally converge to an unbiased estimate. Its performance is experimentally verified using the same apparatus used to perform actual patient diagnoses and a specially-designed physical model of the human cerebrospinal fluid system. (C) 2008 Elsevier Ltd. All rights reserved.