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PURPOSE We wanted to describe the unique issues encountered by our research team in testing an intervention to reduce perinatal depression in real-world community health centers. METHOD We used a case study of an experience in conducting a randomized controlled trial designed to test the effectiveness of a low-cost multimodal psychosocial intervention to reduce prenatal and postpartum depression. Low-income minority women (N = 187) with low-risk pregnancies were randomly assigned to the intervention or treatment as usual. Outcomes of interest were depressive symptoms and social support assessed at 3 months’ postpartum. RESULTS Our intervention was not associated with changes in depressive symptoms or social support. Challenges in implementation were related to participant retention and intervention delivery. Turnover of student therapists affected continuity in participant-therapist relationships and created missed opportunities to deliver the intervention. The academic-community partnership that was formed also required more involvement of health center personnel to facilitate ownership at the site level, especially for fidelity monitoring. While attentive to cultural sensitivity, the project called for more collaboration with participants to define common goals and outcomes. Participatory research strategies could have anticipated barriers to uptake of the intervention and achieved a better match between outcomes desired by researchers and those of participants. CONCLUSION Several criteria for future research planning emerged: assessing what the population is willing and able to accept, considering what treatment providers can be expected to implement, assessing the setting’s capacity to accommodate intervention research, and collecting and using emerging unanticipated data.