In order to investigate the cause of therapeutic failure in an AIDS patient with the highly active antiretroviral therapy (HAART), we examined the sequences of protease (PR) and reverse transcriptase (RT) in 11 consecutive peripheral blood mononuclear cells (PBMC) obtained from the patient for the last 78 months. Nested PCR and direct sequence analysis were performed. Only two resistance mutations (K70R in the RT and L63P in the PR) were detected at the first sample obtained in June 1993 while the patient was on zidovudine (ZDV) monotherapy. From the last sample obtained in December 1999, a total of 14 resistance mutations [4 mutations to ZDV and 2 mutations to Larnivudine (V118I and M184V) in the RT, and 8 mutations to Indinavir (IDV) or Norvir in the PR] were detected. Even after the three drug-combination therapy, the number of resistance mutation gradually increased in the PR and RT (7->11->13->14) as the duration of therapy prolonged. Interestingly, a rare mutation, D67E/G was detected in the RT. These results show that therapeutic failure resulted from multiple drug-resistance mutations in the PR- and RT-coding regions.