Introduction: The effectiveness of antiretroviral therapy (ART) in treating HIV is influenced by the clinical response of patients, which, in turn, impacts the development of drug resistance. This study aimed to assess the correlation between clinical treatment response and resistance to first-line reverse transcriptase inhibitors in HIV patients receiving treatment for ≤12 and >12 months in South Sulawesi, a province in Indonesia. Methods: In this cross-sectional study, 36 people living with HIV (PLHIV) experiencing virological failure (VF) were sampled from HIV services in the province from August 2022 to January 2023. HIV-1 viral RNAs were extracted, sequenced, and analyzed for drug sensitivity and resistance classification using the Stanford University HIV Drug Resistance Database (HIVdb) according to World Health Organization (WHO) recommendations, determining resistance levels and HIV subtypes. Phylogenetic analysis of PR-RT sequences (~1200 base pairs) was performed using the Muscle program and MEGA11 software, utilizing the neighbor-joining method with the Kimura two-parameter model. Results and Discussion: Genotyping of plasma samples revealed that a significant proportion of patients exhibited mutations associated with resistance to both nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs (NNRTIs) (48.6% and 51.4%, respectively). Clinical response indicators, such as initial body mass index and occurrence of opportunistic infections, were found to correlate with specific drug resistance, highlighting the importance of monitoring treatment response. Moreover, virologic response showed strong associations with resistance to specific drugs, suggesting the need for tailored therapeutic approaches. Patient behaviors related to transmission risk factors were also found to be linked to resistance levels, underscoring the multifactorial nature of resistance development. Conclusion: Overall, this study underscores the importance of considering treatment response in managing HIV and suggests implications for optimizing therapy regimens to mitigate resistance emergence. 2025, Bentham Science Publishers