Introduction. Participation in the decision-making process and health literacy may both affect health outcomes; data on how these factors are related among diverse groups are limited. This study examined the relationship between health literacy and decision-making preferences in a medically underserved population. Methods. We analyzed a sample of 576 primary care patients. Multivariable logistic regression was used to examine the independent association of health literacy (measured by the Rapid Estimate of Adult Literacy in Medicine–Revised) and patients’ decision-making preferences (physician directed or patient involved), controlling for age, race/ethnicity, and gender. We tested whether having a regular doctor modified this association. Results. Adequate health literacy (odds ratio [OR] = 1.7; P = 0.009) was significantly associated with preferring patient-involved decision making, controlling for age, race/ethnicity, and gender. Having a regular doctor did not modify this relationship. Males were significantly less likely to prefer patient-involved decision making (OR = 0.65; P = 0.024). Discussion. Findings suggest health literacy affects decision-making preferences in medically underserved patients. More research is needed on how factors, such as patient knowledge or confidence, may influence decision-making preferences, particularly for those with limited health literacy.