The study's objective was to determine the effectiveness of a task-sharing psychological treatment for perinatal depression using non-specialist community health workers. A double-blind individual randomised controlled trial was conducted in two antenatal clinics in the peri-urban settlement of Khayelitsha, Cape Town. Adult pregnant women who scored 13 or above on the Edinburgh Postnatal Depression rating Scale (EPDS) were randomised into the intervention arm (structured six-session psychological treatment) or the control arm (routine antenatal health care and three monthly phone calls). The primary outcome was response on the Hamilton Depression Rating Scale (HDRS) at three months postpartum (minimum 40% score reduction from baseline) among participants who did not experience pregnancy or infant loss (modified intention-to-treat population) (registered on Clinical Trials: NCT01977326). Of 2187 eligible women approached, 425 (19.4%) screened positive on the EPDS and were randomised; 384 were included in the modified intention-to-treat analysis (control: n = 200; intervention: n = 184). There were no significant differences in response on the HDRS at three months postpartum between the intervention and control arm. A task-sharing psychological treatment was not effective in treating depression among women living in Khayelitsha, South Africa. The findings give cause for reflection on the strategy of task-sharing in low-resource settings.