Syndemics occur when populations experience synergistic and multiplicative effects of co-occurring epidemics. Proponents of syndemic theory highlight the importance of understanding the social context in which diseases spread and cogently argue that there are biocultural effects of external stresses such as food insecurity and water insecurity. Thus, a holistic understanding of disease or social vulnerability must incorporate an examination of the emotional and social effects of these phenomena. This paper is a response to the call for a renewed focus on measuring the psycho-emotional and psychosocial effects of food insecurity and water insecurity. Using a mixed-method approach of qualitative interviews and quantitative assessment, including a household demographic, illness, and water insecurity scale, the Household Food Insecurity Access Scale, and the Hopkins Symptoms Checklist-25, this research explored the psycho-emotional effects of water insecurity, food insecurity, and household illness on women and men residing in three low-land districts in Lesotho (n = 75). Conducted between February and November of 2011, this exploratory study first examined the complicated interaction of water insecurity, food insecurity and illness to understand and quantify the relationship between these co-occurring stresses in the context of HIV/AIDS. Second, it sought to separate the role of water insecurity in predicting psycho-emotional stress from other factors, such as food insecurity and household illness. When asked directly about water, qualitative research revealed water availability, access, usage amount, and perceived water cleanliness as important dimensions of water insecurity, creating stress in respondents' daily lives. Qualitative and quantitative data show that water insecurity, food insecurity and changing household demographics, likely resulting from the HIV/AIDS epidemic, are all associated with increased anxiety and depression, and support the conclusion that water insecurity is a critical syndemic dimension in Lesotho. Together, these data provide compelling evidence of the psycho-emotional burden of water insecurity. (C) 2017 Elsevier Ltd. All rights reserved.