U.S. Hispanics, especially women, experience a disproportionate amount of disease burden for depression. This disparity among Hispanic women necessitates examination of factors associated with depression. The objective of this study was to use an adaptation of the Stress Process Model to test whether self-esteem mediated the relationship between Hispanic stress and depressive symptoms. Data for this secondary analysis were from a previous randomized-control HIV prevention trial. Participants were 548 Hispanic women (19-52 years). Data collection measures included the Center for Epidemiological Studies–Depression Scale, Rosenberg Self-Esteem Scale, and Hispanic Stress Scale. The bootstrap method in Mplus 6 was used to test mediation. Results indicated that self-esteem was inversely related to depression, and Hispanic stress was found to be positively related to depression. Self-esteem partially mediated the relationship between stress and depression. Strategies to improve/maintain self-esteem should be considered in future interventions for Hispanic women with depression.