Background: Poor adherence is the main barrier to the effectiveness of HIV medication. The objective of this study was to explore and conceptualize patterns and difficulties in physicians' work with patients' adherence to HIV medication. No previous studies on this subject have directly observed physicians' behavior. Methods: This is a qualitative, cross-sectional study. We used a Grounded Theory approach to let the main issues in physicians' work with patients' adherence emerge without preconceiving the focus of the study. We included physicians from HIV clinics in San Francisco, U.S.A. as well as from Copenhagen, Denmark. Physicians were observed during their clinical work and subsequently interviewed with a semi-structured interview guide. Notes on observations and transcribed interviews were analyzed with NVivo software. Results: We enrolled 16 physicians from San Francisco and 18 from Copenhagen. When we discovered that physicians and patients seldom discussed adherence issues in depth, we made adherence communication and its barriers the focus of the study. The main patterns in physicians' communication with patients about adherence were similar in both settings. An important barrier to in-depth adherence communication was that some physicians felt it was awkward to explore the possibility of non-adherence if there were no objective signs of treatment failure, because patients could feel "accused." To overcome this awkwardness, some physicians consciously tried to "deshame" patients regarding non-adherence. However, a recurring theme was that physicians often suspected nonadherence even when patients did not admit to have missed any doses, and physicians had difficulties handling this low believability of patient statements. We here develop a simple four-step, three-factor model of physicians' adherence communication. The four steps are: deciding whether to ask about adherence or not, pre-questioning preparations, phrasing the question, and responding to the patient's answer. The three factors/determinants are: physicians' perceptions of adherence, awkwardness, and believability. Conclusion: Communication difficulties were a main barrier in physicians' work with patients' adherence to HIV medication. The proposed model of physicians' communication with patients about adherence - and the identification of awkwardness and believability as key issues - may aid thinking on the subject for use in clinical practice and future research.