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Background: Prolonged exposure to stress can lead to substantial suffering, impairment and societal costs. However, access to psychological treatment is limited. Internet-based cognitive behavioral therapy (ICBT) can be effective in reducing symptoms of stress, but little is known of its effects in clinical samples. The aim of this study was to investigate the efficacy of ICBT for patients suffering from chronic stress, operationalized as adjustment disorder (AD) and exhaustion disorder (ED). Methods: A total of 100 adults diagnosed with AD or ED were randomly assigned to a 12-week ICBT (n = 50) or waitlist control condition (n = 50). Primary outcome was the level of perceived stress (PSS). Secondary outcomes included several mental health symptom domains as well as functional impairment and work ability. All outcomes were assessed at baseline, after treatment and at the 6-month follow-up. The study was preregistered at Clinicaltrials.gov: NCT02540317. Results: Compared to the control condition, patients in the ICBT group made large and significant improvements on the PSS (d = 1.09) and moderate to large improvements in secondary symptom domains. Effects were maintained at the 6-month follow-up. There was no significant between-group effect on functional impairment or work ability. Conclusions: A relatively short ICBT is indicated to be effective in reducing stress-related symptoms in a clinical sample of patients with AD and ED, and has the potential to substantially increase treatment accessibility. Results must be replicated, and further research is needed to understand the relationship between symptom reduction, functional impairment and work ability.