The aims of this study are: 1) To analyze the relationship between food insecurity (FI) and adherence to antiretroviral therapy (ART) among people with HIV. 2) To evaluate the contribution of four possible mediators (lack of time due to work and family responsibilities, lack of resources to satisfy needs, psychological distress and side effects of ART) to differences in adherence according to the level of FI. A cross-sectional survey with a convenience sample (n = 557) of people with HIV attending two public institutions in Mexico City was conducted. Variables were assessed by a questionnaire. Logistic regression models were estimated. People with moderate FI were more likely to skip a dose (RM = 2.10) and reported low adherence during the last month (RM = 3.35). Poor adherence among people with FI was explained by the side effects of ART (14.9%), unsatisfied needs (12.5%), lack of time (4.8%) and psychological distress (2%). FI may curtail the benefits of universal access policies because it is associated with lower adherence to ART. An adjustment of health services to reduce the negative effects of FI on adherence to ART is required.