Background: Worldwide, depression is rated as the fourth leading cause of disease burden and is projected to be the second leading cause of disability by 2020. Annual depression-related costs in the United States are estimated at US $210.5 billion, with employers bearing over 50% of these costs in productivity loss, absenteeism, and disability. Because most adults with depression never receive treatment, there is a need to develop effective interventions that can be more widely disseminated through new channels, such as employee assistance programs (EAPs), and directly to individuals who will not seek face-to-face care. Objective: This study evaluated a self-guided intervention, using the MoodHacker mobile Web app to activate the use of cognitive behavioral therapy (CBT) skills in working adults with mild-to-moderate depression. It was hypothesized that MoodHacker users would experience reduced depression symptoms and negative cognitions, and increased behavioral activation, knowledge of depression, and functioning in the workplace.