A 37-year-old homosexual man began antiretroviral combination therapy with didanosine (ddI), lamivudine (3TC) and indinavir (IDV) after being exposed previously to zidovudine (ZDV), ddI and 3TC in different sequential regimens. The patient's viral load did not fall below a detectable level despite his adherence to drug therapy, which was considered optimal. Stavudine (d4T) was prescribed in the third month of treatment instead of ddI without any evident improvement in the treatment response. A point mutation nested PCR assay showed that the patient carried a virus with a codon Q151M mutation, which confers multiple drug resistance to nucleoside analogues. Genetic sequence analysis showed that, despite none of the classically associated mutations to Q151M being present at the beginning of treatment, continuous genetic evolution under selective drug pressure allowed the virus to accumulate mutations at codons 62, 74 and 116 over time. As expected, the CD4+ cell count declined during the study period, and the viral load remained detectable.