The purpose of this study was to elicit patient feedback regarding the perceived clarity and level of difficulty associated with self-report human immunodeficiency virus (HIV) medication adherence measurement tools. HIV-infected patients from clinics in Shreveport, Louisiana, and Chicago, Illinois, were recruited to participate in four focus group discussions. Three groups consisted of patients with limited literacy skills (<ninth-grade reading ability), and one group contained patients with adequate literacy skills (≥ninth-grade reading ability). Five themes emerged: (1) respondent understanding of the term “adherence,” (2) recall, (3) question format, (4) visual aids, and (5) instrument administration. Participants struggled to define adherence, relied on visual cues to identify medications, and had a short recall time frame for missed doses (≤3 days). Most preferred simple question formats and for their physician to assess adherence orally. Patients receiving treatment for HIV infection, especially those with limited literacy skills, may find it difficult to respond to existing HIV medication adherence questionnaires.