BackgroundEvidence-based mental health interventions to support healthcare workers (HCWs) in crisis settings are scarce.ObjectiveTo evaluate the capacity of a mental health intervention in reducing anxiety and depression symptoms in HCWs, relative to enhanced care as usual (eCAU), amidst the COVID-19 pandemic.MethodsWe conducted an analyst-blind, parallel, multicentre, randomised controlled trial. We recruited HCWs with psychological distress from Madrid and Catalonia (Spain). The intervention arm received a stepped-care programme consisting of two WHO-developed interventions adapted for HCWs: Doing What Matters in Times of Stress (DWM) and Problem Management Plus (PM+). Each intervention lasted 5 weeks and was delivered remotely by non-specialist mental health providers. HCWs reporting psychological distress after DWM completion were invited to continue to PM+. The primary endpoint was self-reported anxiety/depression symptoms (Patient Health Questionnaire-Anxiety and Depression Scale) at week 21.FindingsBetween 3 November 2021 and 31 March 2022, 115 participants were randomised to stepped care and 117 to eCAU (86% women, mean age 37.5). The intervention showed a greater decrease in anxiety/depression symptoms compared with eCAU at the primary endpoint (baseline-adjusted difference 4.4, 95% CI 2.1 to 6.7; standardised effect size 0.8, 95% CI 0.4 to 1.2). No serious adverse events occurred.ConclusionsBrief stepped-care psychological interventions reduce anxiety and depression during a period of stress among HCWs.Clinical implicationsOur results can inform policies and actions to protect the mental health of HCWs during major health crises and are potentially rapidly replicable in other settings where workers are affected by global emergencies.Trial registration numberNCT04980326.