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The U.S. Department of Health and Human Services human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) treatment guidelines are modified several times per year to reflect the rapid evolution of the field (e.g., emergence of new antiretroviral drugs). As such, a treatment- decision support system that is capable of self-learning is highly desirable. Based on the fuzzy discrete event system (FDES) theory that we recently created, we have developed a self-learning HIV/AIDS regimen selection system for the initial round of combination antiretroviral therapy, one of the most complex therapies in medicine. The system consisted of a treatment objectives classifier, fuzzy finite state machine models for treatment regimens, and a genetic-algorithm-based optimizer. Supervised learning was achieved through automatically adjusting the parameters of the models by the optimizer. We focused on the four historically popular regimens with 32 associated treatment objectives involving the four most important clinical variables (potency, adherence, adverse effects, and future drug options). The learning targets for the objectives were produced by two expert AIDS physicians on the project, and their averaged overall agreement rate was 70.6%. The system's learning ability and new regimen suitability prediction capability were tested under various conditions of clinical importance. The prediction accuracy was found between 84.4% and 100%. Finally, we retrospectively evaluated the system using 23 patients treated by 11 experienced nonexpert faculty physicians and 12 patients treated by the two experts at our AIDS Clinical Center in 2001. The overall exact agreement between the 13 physicians' selections and the system's choices was 82.9% with the agreement for the two experts being both 100%. For the seven mismatched cases, the system actually chose more appropriate regimens in four cases and equivalent regimens in another two cases. It made a mistake in one case.- - These (preliminary) results show that 1) the System outperformed the nonexpert physicians and 2) it performed as well as the expert physicians did. This learning and prediction approach, as well as our original FDESs theory, is general purpose and can be applied to other medical or nonmedical problems.