A crucial factor in the success of treatment for patients with Human Immunodeficiency Virus (HIV) is adherence to antiretroviral (ARV) therapy among People Living with HIV/AIDS (PLWHA). Adherence issues remain a persisting problem with multifaceted causes. There are many studies on variables related to ARV therapy adherence, but no study has been found on spiritual well-being and distress tolerance in ARV therapy adherence. This study aims to determine the relationship between distress tolerance and spiritual well-being on adherence to ARV therapy in PLWHA. This research used a quantitative approach with a cross-sectional design. The sample collection process followed a consecutive sampling technique, with data gathered from 129 participants at the South Lampung Regional General Hospital located in Indonesia. Data collection was conducted using three questionnaires administered by the interviewer, which assessed distress tolerance using the Miller–Smith Rating Scale For Stress Tolerance (MSRS-ST), evaluated spiritual Well-Being using the Spiritual Well-Being Scale (SWBS), and gauged ARV therapy adherence using the Medication Adherence Rating Scale (MARS). Data analysis using a simple logistic regression with a 95% confidence interval (CI) showed a significant relationship between distress tolerance (p-value 0.002) and spiritual well-being (p-value 0.036) towards ARV therapy adherence in PLWHA. The results of multiple logistic regression yielded distress tolerance as the most dominant and influential variable in this research. Distress tolerance and spiritual well-being impact adherence to ARV therapy in PLWHA. Suggestions for healthcare services should consider these factors to decrease the risk of non-adherence to therapy and inadvertently heighten mortality risk.