The emergence of drug resistant pathogens can reduce the efficacy of drugs commonly used to treat infectious diseases. Human immunodeficiency virus (HIV) is particularly sensitive to drug selection pressure, rapidly evolving into drug resistant variants on exposure to anti-HIV drugs. Over 200 mutations within the genetic material of HIV have been shown to be associated with drug resistance to date, and complex mutational patterns have been found in HIV isolates from infected patients exposed to multiple antiretroviral drugs. Genotyping is commonly used in clinical practice as a tool to identify drug resistance mutations in HIV from individual patients. This information is then used to help guide the choice of future therapy for patients whose drug regimen is failing because of the development of drug resistant HIV. Many sets of rules and algorithms are available to predict loss of susceptibility to individual antiretroviral drugs from genotypic data. Although this approach has been helpful, the interpretation of genotypic data remains challenging. We describe here the development and application of ANN models as alternative tools for the interpretation of HIV genotypic drug resistance data. A large amount of clinical and virological data, from around 30,000 patients treated with antiretroviral drugs, has been collected by the HIV Resistance Response Database Initiative (RDI, www.hivrdi.org) in a centralized database. Treatment change episodes (TCEs) have been extracted from these data and used along with HIV drug resistance mutations as the basic input variables to train ANN models. We performed a series of analyses that have helped define the following: (1) the reliability of ANN predictions for HIV patients receiving routine clinical care; (2) the utility of ANN models to identify effective treatments for patients failing therapy; (3) strategies to increase the accuracy of ANN predictions; and (4) performance of ANN models in comparison to the rules-based methods currently in use.