Background: Depression is under-diagnosed and under-treated in most areas of the US. New York City is currently looking to close gaps in identifying and treating depression through the adoption of a screening and collaborative care model deployed throughout the city. Methods: We examine the cost-effectiveness of universal two-stage screening with the 2- and 9-item Patient Health Questionnaires (PHQ-2 and PHQ-9) in New York City followed by collaborative care for those who screen positive. We conducted microsimulations on hypothetical adult participants between ages 20 and 70. Results: The incremental cost-effectiveness of the interventions over the average lifespan of a 20-year-old adult in NYC is approximately $1,726/QALY gained (95% plausible interval: cost-saving, $10,594/QALY gained). Conclusions: Two-stage screening coupled with collaborative care for depression in the clinical setting appears to be significantly less expensive than most clinical preventive interventions, such as HIV screening in high-risk patients. However, effectiveness is dependent on the city’s ability to manage scale up of collaborative care models. © 2017 Jiao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.