We have investigated the frequency of resistance mutations to highly active antiretroviral therapy (HAART) in 37 Korean HIV-1-infected patients, 22 of whom had experienced previous monotherapy. CD4(+) T cell counts significantly increased from 135 +/- 110/microl to 523 +/- 259/microl for 39 +/- 3 months by HAART (p < 0.0001). Over 39 +/- 3 months of HAART, 18 of 37 patients (48.6%) harbored drug resistance mutations. The most frequently observed mutation was M184V (24.3%, 9/37). Seven of 35 patients (20.0%) exposed to protease inhibitors and 2 of 11 (18.2%) exposed to nonnucleoside reverse transcriptase inhibitors developed resistance mutations to their respective drugs. When we measured HIV-1 RNA viral loads over 30 months of HAART in 31 patients, we found that 13 patients (41.9%) showed virological treatment failure, with viral load >400 copies/ml. In conclusion, we found that the frequency of resistance mutations to antiretroviral drugs over 30 months was high in HAART-treated patients. As the first report on resistance mutations to HAART in Korea, our data suggest that genotyping-guided treatment as well as education for compliance are required for better care.