Background: Suboptimal rates of non-adherence have been reported in leukemia patients taking oral anticancer agents (OAAs), largely attributed to treatment-related symptoms (TRS). This survey was conducted to describe the complex relationship between adherence, TRS, and health-related quality of life (HRQOL). Methods: This is a single arm, observational, prospective, longitudinal study. Patients with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphoid leukemia (CLL) on OAAs completed a telephone survey, which included Wilson’s 3-item medication adherence measure, the PROMIS 10-item Global Health Scale (domains: overall QOL, physical/mental/social health), and assessment of TRS using PRO-CTCAE. This survey was repeated three times, two to three months apart. Optimal adherence was defined as greater than 90% per Wilson’s measure. Spearman’s correlation, chi-square tests, as appropriate, to evaluate the association between medication adherence and HRQOL. Results: 77 patients completed the first survey, of which 60.3% were male, with an average age of 62 years old. Diagnoses were: CML (n=28), CLL (n=19), AML (n=19), and ALL (n=11). Optimal adherence rates declined from 70.2% in the 1^st survey to 55% by the 3^rd survey, whereas HRQOL measures remained stable over time. Most patients (92.2%, n= 71) reported at least one TRS with 42.25% (n= 30) reporting ≥6 symptoms. Patients without TRS were more likely to be adherent than those with symptoms (100% vs. 67%, p=0.17). Specifically, patients with no pain were associated with higher adherence (p= 0.084). Those who rated their mental health and overall quality of life (QOL) as ‘excellent,’‘very good,’ or ‘good’ had numerically a higher adherence rate (73% with optimal adherence) than those rating it as ‘fair’ or ‘poor,’ (59-61% had optimal adherence), although not statistically significant. The number of TRS reported from PRO-CTCAE significantly affected patients’ reported QOL: patients reporting 0-5 number of TRS were more likely to report higher QOL (‘excellent,’‘very good,’ or ‘good’) than those reporting ≥6 TRS (p = 0.0004). Conclusions: Adherence rates in leukemia patients on OAAs were suboptimal and declined over time. TRS were common and inversely associated with HRQOL, even though adherence was not strongly correlated: patients with high adherence still reported fair or poor HRQOL. Given the numerous and varied factors contributing to non-adherence and HRQOL issues in leukemia patients, a multi-modality support program is essential.