Background: Adequate informed consent (IC) comprehension is an ethical right prior to participation in clinical trials. Research investigating IC comprehension and associations with social determinants of health (SDoH) is lacking. We assessed whether SDoH and related contextual factors were associated with parental IC comprehension in therapeutic childhood cancer clinical trials. Methods: We prospectively enrolled parents of children with newly-diagnosed cancer. Univariable and multivariable regression were used to assess whether objective IC comprehension and related domains (Purpose/Procedures/Randomization, Risks/Benefits, Alternatives, and Voluntariness) were associated with SDoH (ethnicity, marital status, language, education attainment, employment, insurance, socio-economic status, health literacy [HL]) and contextual factors (cancer type, voluntariness, satisfaction with IC). Results: Of 223 parents included, 112 (50%) were Hispanic and 38% of Hispanics were monolingual Spanish-speaking. In adjusted multivariable analyses, limited HL was significantly associated with lower overall IC comprehension (β = -7.22; 95% CI, -10.9 to -3.59; P < 0.001) and lower comprehension of Purpose/Procedures/Randomization (β = -7.53; 95% CI, -11.3 to -3.73; P < 0.001), Risks/Benefits (β = -8.14; 95% CI, -15.5 to -0.772; P = 0.031), and Alternatives (β = -17.0; 95% CI, -30.5 to -3.57; P = 0.013). Preferred Spanish language of written/verbal medical information was significantly associated with lower comprehension of Purpose/Procedures/Randomization (β = -8.50; 95% CI, -15.1 to -1.89; P = 0.012) and Voluntariness (β = -20.1; 95% CI, -34.9 to -5.33; P = 0.008). Lower satisfaction with informed consent (β = 0.988; 95% CI, 0.460 to 1.52; P < 0.001) and single marital status (β = -4.42; 95% CI, -7.81 to -1.02; P = 0.011) were significantly associated with lower IC comprehension. Conclusions: Among parents of children with newly diagnosed cancer who provided consent for their child’s participation in a therapeutic clinical trial, limited HL was consistently associated with lower IC comprehension in all domains analyzed, except for Voluntariness. Spanish language preference for medical information was associated with lower comprehension of two domains; and lower satisfaction was associated with lower overall IC comprehension. These findings suggests that parents with limited HL, limited English-proficiency, and lower satisfaction may not fully comprehend the IC and thereby not truly make informed decisions. Our findings highlight the potential role of language-concordant interventions tailored to the participant’s HL level in order to ultimately improve IC comprehension and contribute to a reduction of disparities in clinical trial participation and promote equitable translation of discoveries and treatments to underserved groups.