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Abstract Background Depression is a prevalent and serious mood disorder and a major source of disability adjusted life years (DALY) in Uganda. Furthermore, evidence from Uganda and other countries throughout sub-Saharan Africa suggests that nearly a third of persons living with human immunodeficiency virus (HIV) suffer from depression and it adversely affects healthcare seeking behavior. The high burden of disease attributable to depression makes data on the prevalence of depression in Uganda, a country with a generalized HIV epidemic, a public health priority. This paper describes the psychometric properties of the Center for Epidemiologic Studies-Depression (CES-D) measure when administered to men and women residing in three fishing communities along the shore of Lake Victoria. Methods We applied methods based on item response theory and classical test theory approaches to assess individual item characteristics, conducted exploratory factor analysis and assessed internal reliability, and construct and content validity of the measure. All analyses were performed in R Studio. Results The study sample consisted of 300 residents of fishing communities in Wakiso District, Uganda. Fifty-six percent of the sample was female and 19.7% reported being HIV positive. Seven items of the measure that did not perform well, either because they could not differentiate between levels of the latent trait or because they did not map onto the primary factor, were removed from the scale. A single factor structure best fit our final set of 13-items and we found an overall coefficient alpha of 0.89, indicating high internal consistency in this population. Conclusions Based on our findings, we recommend that future use of the CES-D in this population utilize our revised scale with the final set of 13-items. The addition of other measures that can improve the rigor of CES-D validation efforts, such as inclusion of a clinical depression measure and administration in both a clinical and a general population sample in this setting are needed.