As the public health importance of depression grows in low-income countries, development of culturally relevant and valid measurement tools is increasingly necessary to inform effective interventions. This research was embedded within the Family Health and Wealth Study, an ongoing multi-country cohort study. We use mixed methods to assess the reliability and various aspects of validity, including cultural relevance, of a 10-item version of the Center for Epidemiologic Studies Depression (CES-D 10) Scale among men and women of reproductive age in Kumasi, Ghana. The scale demonstrated adequate internal consistency reliability, and factor analysis supported a one-factor model for both men and women in the study setting. However, qualitative findings highlighted several additional relevant symptom groups in the study population that were not included in the scale: loss of concentration, loss of appetite, suicidal ideation and becoming quiet or withdrawn. Although quantitative analyses indicated that the CES-D 10 scale demonstrated adequate reliability and validity as a measure of depressive symptoms, qualitative analyses revealed that this scale failed to fully capture depression as it is conceptualized in the study community. Our results underline the importance of integrating culturally-specific information on mental health when developing and adapting measurement tools in new settings.