Our objective was to assess the utility of an assessment battery capturing health literacy (HL) and biopsychosocial determinants of health in predicting 30-day readmission in comparison to a currently well-adopted readmission risk calculator. We also sought to capture the distribution of inpatient HL, with emphasis on inadequate and marginal HL (an intermediate HL level). A prospective observational study was conducted to obtain HL and biopsychosocial data on general medicine inpatients admitted to the UCLA health system. Five hundred thirty-seven subjects were tracked prospectively for 30-day readmission after index hospitalization. HL was significantly better at predicting readmission compared to LACE + (Length, admission acuity, comorbidities, emergency room visits) alone (P = .013). A multivariate model including education, insurance, and language comfort was a strong predictor of adequate HL (P < .001). In conclusion, HL offered significant improvement in risk stratification in comparison to LACE + alone. Patients with marginal HL were high-risk, albeit difficult to characterize. Incorporating robust HL and biopsychosocial determinant assessments may allow hospital systems to allocate educational resources towards at-risk patients, thereby mitigating readmission risk.