Objective: Health literacy is an important predictor of individuals’ health, medical adherence, and health-related decision making. This study investigated the predictors of health literacy among Deaf American Sign Language (ASL) users. Methods: 408 Deaf ASL users and 445 Hearing English speakers were administered the Newest Vital Sign, a measure of health literacy available in both English and ASL, along with assessments of language proficiency and reading skills. Results: Deaf participants had 3.7 times greater odds of inadequate health literacy (95 % CI: 2.7, 4.9) compared to their hearing counterparts. Binary logistic regression revealed that Deaf participants’ ASL proficiency and English reading grade equivalent explained 34.2 % (Nagelkerke R2) of the variance in health literacy, χ2(2) = 101.520, p  .001. Among hearing participants, by contrast, English proficiency and English reading grade equivalent explained 47.8 % of the variance in health literacy, χ2(2) = 171.071, p  .001. Conclusions: Deaf people are at risk for having greater difficulty to find, understand, and use information and services to inform health-related decisions and actions for themselves and others. Practice implications: Health professionals and health systems should allocate resources to mitigate health literacy barriers among Deaf people and make health information more available in ASL.