Background: Health literacy (HL) is the individual’s ability to find and use information and services to make health decisions. Limited HL is associated with poorer outcomes. HL is vastly understudied in childhood cancer. Thus, we investigated HL and associations with Social Determinants of Health in caregivers of children with newly diagnosed cancer and of childhood cancer survivors. Methods: We conducted a prospective cross-sectional study in caregivers of children with newly diagnosed cancer and caregivers of childhood cancer survivors at Rady Children’s Hospital (2016-2019). Caregivers completed questionnaires in-person to assess sociodemographics, acculturation and HL with the Test of Functional Health Literacy (S- TOFHLA) and the Newest Vital Sign (NVS). Results: 459 caregivers were enrolled (199 caregivers of children with newly diagnosed cancer and 260 caregivers of childhood cancer survivors). 56% (n=256) were Hispanic and of those, 38% were Spanish-speaking, and 53% had low acculturation. Hispanics, compared to non-Hispanic Whites, had lower S-TOFHLA and NVS scores (p<0.001). Moreover, Hispanics had lower income (p<0.001) and lower education attainment (p<0.001), and were more likely to have public insurance (p<0.001), and unmarried marital status (p<0.001). Adjusted multivariable regression showed a higher odds ratio (OR) of limited HL in caregivers with education level of high school or less (OR=3.040, 95%CI:1.308,7.087), unmarried marital status (OR=2.573, 95%CI:1.065, 6.424), and Spanish as preferred language (OR=5.072, 95%CI:1.960,14.018). Conclusions: We found that Hispanic and Spanish-speaking caregivers of children with newly diagnosed cancer and caregivers of childhood cancer survivors were at higher risk for limited HL. Hispanics were also more likely to have public insurance, unmarried marital status, and lower education level. In underserved groups such as these, HL is an especially critical component of navigating cancer care and making informed health decisions. It is, therefore, essential to direct future research efforts towards developing interventions to improve HL in underserved populations to improve cancer clinical outcomes.