Food insecurity and drug use are closely connected in the context of poverty, and both have been suggested to interfere with HIV medication adherence among people living with HIV/AIDS (PLWH). Yet the potential interaction between the two factors on adherence has not been examined. For this study we collected longitudinal data on HIV medication adherence among PLWH in Atlanta, GA, to assess a possible synergistic effect between the two factors on HIV medication adherence. People informed about the study came to the research site and completed an audio computer-assisted self-interview and instructions for pill counting. Over the next 5 weeks participants received three unscheduled follow-up phone assessments conducted 2 weeks apart to collect pill counts of their HIV medication. The prevalence of food insecurity was 60 % (488) and that of drug use was 33 % (274) in the sample of 809 participants. Among 770 participants who completed follow-up phone assessments, both food insecurity and drug use were associated with HIV medication adherence after adjusting for socio-demographic characteristics. The negative association between drug use and adherence persisted after further adjusting for health-related characteristics. Moreover, drug use appeared to moderate the effect of food insufficiency on adherence, with drug users who were food insufficient being the least likely to achieve 85 % adherence. Results from the current study demonstrate a synergism between food insecurity and drug use that may impede adherence among PLWH. The findings imply that the disruptive effects of food insecurity and drug use on adherence are likely to be intensified with the presence of each other, and encourage interventions to address the problem of HIV medication adherence from a multi-faceted perspective that takes into account detrimental combination of problem factors.