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The impact of depression on the workplace has been widely observed in studies examining absenteeism and reduced productivity during days at work. However, there is little scientific evidence about whether depression interventions are cost-beneficial to employers.We construct a cost–benefit analysis of depression treatment under different workplace assumptions better reflecting the nature of employment.Data from a randomized controlled trial in which employed primary care patients with depression were treated in practices randomly assigned to an enhanced treatment intervention or usual care were used to construct a cost–benefit model from an employer perspective under different assumptions regarding employment.A national sample of 198 workers employed in a range of positions by companies was studied.Benefits included self-reported productivity and absenteeism; costs included intervention and treatment costs. Net benefit was calculated under different scenarios and return on investment (ROI) is derived.Enhanced depression treatment resulted in an average net benefit to the employer of $30 per participating worker in Year 1 of the intervention and $257 per participating worker in Year 2, for an estimated ROI during the 2-year period of 302%. ROI increased in firms that rely on team production, hire more costly substitute labor, or realize penalties for output shortfalls. ROI decreased in firms that have a large fraction of employees with dependent coverage and experience high turnover rates. Results also are sensitive to how subjectively reported productivity is valued.Many employers will receive a potentially significant ROI from depression treatment models that improve absenteeism and productivity at work.