Background There has been an increase in the use of oral agents for the treatment of hematologic malignancies. Though clinically efficacious and convenient, oral therapies often have higher out-of-pocket cost than intravenous medications due to differences in insurance coverage. High financial burden and sequelae thereof, known as financial toxicity (FT), can negatively impact patient mood, adherence, quality of life (QoL), and outcomes. We present cross-sectional data from a longitudinal survey to evaluate the economic, psychosocial, and QoL impact of oral anti-cancer medications (OAMs) in the treatment of hematologic malignancies. Methods We used database query to identify patients at a midwestern, tertiary care, academic medical center who were 18 years or older and were prescribed Enasidenib, Ivosidenib, Venetoclax, Gilteritinib, Midostaurin, Ibrutinib, Acalabrutinib, Imatinib, Nilotinib, Ponatinib, Bosutinib, Duvelisib, or Idelalisib within the past 3 months. Chart review confirmed medication initiation within the past 3 months for a diagnosis of MDS, AML, CML, ALL, CLL, HL, or NHL. Patients were recruited by phone and consented by email. Consenting patients were sent an 85-item online survey assessing sociodemographic information, treatment-related information, and validated surveys, including the Functional Assessment of Cancer Therapy (FACT-G7) and Comprehensive Score for Financial Toxicity (COST) questionnaires. Participants received a follow-up survey 3 months after completing the initial survey. Statistical analysis was performed with GraphPad Prism 9 by Spearman's rank correlation, Mann-Whitney U test, or Kruskal-Wallis H test as appropriate. Results Between November 2021 and April 2023, 528 patients were identified, of whom 152 were eligible for participation and 28 consented and completed the initial survey (18.4%). Demographics are reported in Table 1. The group was predominantly male (64.3%), white (92.9%), married (78.6%), college-educated (64.3%), and financially stable (50% with annual income over $100,000). In the six months prior to diagnosis, 57.1% of participants were working full time and 35.7% were retired. At the time of survey completion, 25% were working full time, 50% were retired, and 14.3% were disabled or unable to work due to health. All participants were insured (60.7% Medicare, 35.7% private insurance). All participants on Medicare had Part A and B coverage, and 82.4% had Part D coverage. All but 1 participant had prescription drug coverage. AML (32.1%), CLL (25%), and CML (17.9%) were the most common diagnoses. Venetoclax (46.6%) was the most common OAM. Results are summarized in Table 2. Those with a history of depression or anxiety had no difference in financial stress, experiencing cancer as a financial hardship, QoL satisfaction, or bother from side effects (SE) as those without such history. Income was inversely associated with identifying cancer as a financial hardship (rs -0.485; 95% CI, -0.732 to -0.125) and with pain (rs -0.389; 95% CI, -0.678 to -0.007). Income had no correlation with QoL satisfaction or bother from SE. Insurance coverage had no association with financial stress, seeing cancer as a financial hardship, QoL satisfaction, or bother from SE. Those disabled or unable to work felt more financial stress than those who were retired (P=0.018). They also saw cancer as more of a financial hardship than those who either worked full time or were retired (P=0.005). Those who had a family member stop working or reduce work hours had lower income (P=0.009), greater financial stress (P=0.015), worse QoL satisfaction (P=0.013), and increased bother from SE (P=0.017) than those who did not. Financial stress was negatively associated with QoL satisfaction (rs -0.552; 95% CI, -0.775 to -0.206) and positively associated with bother from SE (rs 0.469; 95% CI, 0.105 to 0.772). Experiencing cancer as a financial hardship was negatively associated with QoL satisfaction (rs -0.517; 95% CI, -0.755 to -0.159). Conclusions In this well-resourced cohort taking OAMs to treat hematologic malignancies, there were multiple indicators of FT. Patient or family loss of employment was notably associated with financial stress and hardship. Financial stress and hardship were associated with worse satisfaction with QoL and worse experience of SE. Further study should define change in these features over time and interventions to mitigate distress.