Spanish-dominant Hispanics in the United States face challenges to reaching optimal antiretroviral therapy adherence due to cultural-linguistic factors and motivation to adhere to medication. The authors used a mixed-methods approach using interviews guided by the Information-Motivation-Behavior Skills model to investigate motivational aspects associated with adherence in HIV-positive Spanish-dominant Hispanics. Twenty-five patients (aged 29–63 years, mean = 47.7 years) from a clinic serving the indigent/noninsured Hispanics were interviewed. Analyses revealed HIV stigma, the role of familia (family), social support, and depression were major themes within cultural contexts relevant to understanding motivational factors related to adherence. In addition, many participants reported worry about being seen taking HIV medications, that the medications will harm their health or will affect their looks, and medication side effects. The findings elucidate motivational factors and the influence of culture in adherence decision-making. For HIV-positive Spanish-dominant Hispanics, intervening to improve adherence will likely be most effective by targeting potential culturally relevant motivational barriers.