BACKGROUND: Patient portals have the potential to support self-management for chronic diseases and improve health outcomes. With the rapid rise in adoption of patient portals spurred by meaningful use incentives among safety net health systems (a health system or hospital providing a significant level of care to low-income, uninsured, and vulnerable populations), it is important to understand the readiness and willingness of patients and caregivers in safety net settings to access their personal health records online. OBJECTIVE: To explore patient and caregiver perspectives on online patient portal use before its implementation at San Francisco General Hospital, a safety net hospital. METHODS: We conducted 16 in-depth interviews with chronic disease patients and caregivers who expressed interest in using the Internet to manage their health. Discussions focused on health care experiences, technology use, and interest in using an online portal to manage health tasks. We used open coding to categorize all the barriers and facilitators to portal use, followed by a second round of coding that compared the categories to previously published findings. In secondary analyses, we also examined specific barriers among 2 subgroups: those with limited health literacy and caregivers. RESULTS: We interviewed 11 patients and 5 caregivers. Patients were predominantly male (82%, 9/11) and African American (45%, 5/11). All patients had been diagnosed with diabetes and the majority had limited health literacy (73%, 8/11). The majority of caregivers were female (80%, 4/5), African American (60%, 3/5), caregivers of individuals with diabetes (60%, 3/5), and had adequate health literacy (60%, 3/5). A total of 88% (14/16) of participants reported interest in using the portal after viewing a prototype. Major perceived barriers included security concerns, lack of technical skills/interest, and preference for in-person communication. Facilitators to portal use included convenience, health monitoring, and improvements in patient-provider communication. Participants with limited health literacy discussed more fundamental barriers to portal use, including challenges with reading and typing, personal experience with online security breaches/viruses, and distrust of potential security measures. Caregivers expressed high interest in portal use to support their roles in interpreting health information, advocating for quality care, and managing health behaviors and medical care. CONCLUSIONS: Despite concerns about security, difficulty understanding medical information, and satisfaction with current communication processes, respondents generally expressed enthusiasm about portal use. Our findings suggest a strong need for training and support to assist vulnerable patients with portal registration and use, particularly those with limited health literacy. Efforts to encourage portal use among vulnerable patients should directly address health literacy and security/privacy issues and support access for caregivers.