To assess a two-question screening tool, the Patient Health Questionnaire-2 (PHQ-2), for identifying depressive symptomatology in economically disadvantaged mothers of children in pediatric settings and to explore risk factors associated with a positive depression screen. A convenience sample of mothers was enrolled at an inner city well-child clinic with children age 3 days to 5 years. The PHQ-2 and Edinburgh Postnatal Depression Scale (EPDS) (as reference scale) were completed. Ninety-four mothers participated. Agreement of the PHQ-2 and EPDS was moderate. The sensitivity of the PHQ-2 for identifying a positive screen on the EPDS was 43.5%; the specificity was 97.2%. The sensitivity of the PHQ-2 was higher for mothers with education beyond high school compared to those with less education. Perceived lack of support with child care and having two or more children were associated with a positive screen. The rate of positive screen was similar for mothers with infants and with older children. Given the low sensitivity of the PHQ-2 in lower educated mothers, additional research in populations with varying sociodemographic characteristics is indicated. Similar rates of symptoms for mothers within and beyond the postpartum period and mothers previously screened support the need for periodic screening.