Adherence to iron chelation therapy (ICT) is fundamental for preventing iron overload complications and maintaining health-related quality of life (HRQoL) in transfusion-dependent thalassemia (TDT) patients. This study aimed to evaluate adherence, HRQoL, and their association among Malaysian TDT patients. Cross-sectional research was performed among TDT patients aged 18 years and above in Hospital Ampang, Selangor. The adherence and the HRQoL (SF-36) were evaluated using validated instruments. Correlation analyses were carried out to determine the association between ICT adherence and HRQoL. The study recruited 162 patients, with 46.91% (N=76) of respondents reporting being adherent. The mean SF-36 score for TDT patients is 74.58. Remarkably, adherent patients exhibit significantly higher HRQoL (mean SF-36 score 79.21) assessed by the SF-36 questionnaire versus nonadherent patients (mean SF-36 score 69.47) (p=0.00). The findings also revealed a significant positive correlation between female (p=0.032), employed (p=0.003), and age (p=0.050) factors with the patient’s HRQoL. The rate of ICT adherence for adult TDT patients is suboptimal and non-adherent to ICT has significantly compromised HRQoL. Enhancing the rate of ICT adherence through interventions such as patient counseling and support programs may lead to enhanced HRQoL outcomes for the TDT population.