BACKGROUND: Approximately one-half of American adults exhibit low health literacy and thus struggle to find and use health information. Low health literacy is associated with negative outcomes including overall poorer health. Health information technology (HIT) makes health information available directly to patients through electronic tools including patient portals, wearable technology, and mobile apps. The direct availability of this information to patients, however, may be complicated by misunderstanding of HIT privacy and information sharing. OBJECTIVE: The purpose of this study was to determine whether health literacy is associated with patients' use of four types of HIT tools: fitness and nutrition apps, activity trackers, and patient portals. Additionally, we sought to explore whether health literacy is associated with patients' perceived ease of use and usefulness of these HIT tools, as well as patients' perceptions of privacy offered by HIT tools and trust in government, media, technology companies, and health care. This study is the first wide-scale investigation of these interrelated concepts. METHODS: Participants were 4974 American adults (n=2102, 42.26% male, n=3146, 63.25% white, average age 43.5, SD 16.7 years). Participants completed the Newest Vital Sign measure of health literacy and indicated their actual use of HIT tools, as well as the perceived ease of use and usefulness of these applications. Participants also answered questions regarding information privacy and institutional trust, as well as demographic items. RESULTS: Cross-tabulation analysis indicated that adequate versus less than adequate health literacy was significantly associated with use of fitness apps (P=.02), nutrition apps (P<.001), activity trackers (P<.001), and patient portals (P<.001). Additionally, greater health literacy was significantly associated with greater perceived ease of use and perceived usefulness across all HIT tools after controlling for demographics. Regarding privacy perceptions of HIT and institutional trust, patients with greater health literacy often demonstrated decreased privacy perceptions for HIT tools including fitness apps (P<.001) and nutrition apps (P<.001). Health literacy was negatively associated with trust in government (P<.001), media (P<.001), and technology companies (P<.001). Interestingly, health literacy score was positively associated with trust in health care (P=.03). CONCLUSIONS: Patients with low health literacy were less likely to use HIT tools or perceive them as easy or useful, but they perceived information on HIT as private. Given the fast-paced evolution of technology, there is a pressing need to further the understanding of how health literacy is related to HIT app adoption and usage. This will ensure that all users receive the full health benefits from these technological advances, in a manner that protects health information privacy, and that users engage with organizations and providers they trust.