Food insecurity is highly prevalent in HIV-infected populations, and analyses utilizing multiple assessments of food security to predict CD4 change are lacking. Five hundred Ninety-two patients with ≥ 4 food security assessments were followed prospectively. In the final model, for patients using antiretroviral therapy, increases in CD4 counts were on average 99.5 cells less for individuals with at least 1 episode of food insecurity compared with those consistently food secure (P < 0.001). Other sociodemographic factors were not predictive. Repeated assessments of food security are potent predictors of treatment response notwithstanding antiretroviral therapy use. Potential mechanisms for this association are proposed.