Background: High-frequency Deep Brain Stimulation (DBS) of the subcallosal cingulate (SCC) region is an emerging strategy for treatment-resistant depression (TRD). This study examined changes in SCClocal field potentials (LFPs). The LFPs were recorded fromthe DBS leads following transient, unilateral stimulation at the neuroimaging-defined optimal electrode contact. The goal was identifying a putative electrophysiological measure of target engagement during implantation. Methods: Fourteen consecutive patients underwent bilateral SCC DBS lead implantation. LFP recordings were collected from all electrodes during randomized testing of stimulation on each DBS contact (eight total). Analyses evaluated changes in spectral power before and after 3min of unilateral stimulation at the contacts that later facilitated antidepressant response, as a potential biomarker of optimal contact selection in each hemisphere. Results: Lateralized and asymmetric power spectral density changes were detected in the SCC with acute unilateral SCC stimulation at those contacts subsequently selected for chronic, therapeutic stimulation. Left stimulation induced broadband ipsilateral decreases in theta, alpha, beta and gamma bands. Right stimulation effects were restricted to ipsilateral beta and gamma decreases. These asymmetric effects contrasted with identical white matter stimulation maps used in each hemisphere. More variable ipsilateral decreases were seen with stimulation at the adjacent “suboptimal” contacts, but changes were not statistically different from the “optimal” contact in either hemisphere despite obvious differences in impacted white matter bundles. Change in theta power was, however, most robust and specific with left-sided optimal stimulation, which suggested a putative functional biomarker on the left with no such specificity inferred on the right. Conclusion: Hemisphere-specific oscillatory changes can be detected from the DBS lead with acute intraoperative testing at contacts that later engender antidepressant effects. Our approach defined potential target engagement signals for further investigation, particularly left-sided theta decreases following initial exposure to stimulation. More refined models combining tractography, bilateral SCCLFP, and cortical recordings may further improve the precision and specificity of these putative biomarkers. It may also optimize and standardize the lead implantation procedure and provide input signals for next generation closed-loop therapy and/or monitoring technologies for TRD.