Acute mental health symptoms experienced during oil spill response work are understudied, especially among nonlocal responders. We assessed potential risk factors for acute mental health symptoms and tobacco initiation among U.S. Coast Guard responders to the 2010 Deepwater Horizon (DWH) oil spill who completed a deployment exit survey. Cross-sectional associations among responder characteristics, deployment-related stressors (deployment duration, timing, crude oil exposure, physical symptoms, injuries), and professional help-seeking for stressors experienced with concurrent depression/anxiety and tobacco initiation were examined. Log-binomial regression was used to calculate adjusted prevalence ratios (aPRs) and 95% confidence intervals. Sensitivity analyses excluded responders with a history of mental health conditions using health encounter data from the Military Health System Data Repository. Of the 4,855 responders, 75.5% were deployed from nonlocal/non-Gulf home stations, 5.8% reported concurrent depression and anxiety, and 2.8% reported the initiation of any tobacco product during oil spill response. Self-report of concurrent depression and anxiety was more prevalent among female responders and positively associated with longer deployments, crude oil exposure via inhalation, physical symptoms and injuries, and professional help-seeking during deployment, aPRs = 1.54-6.55. Tobacco initiation was inversely associated with older age and officer rank and positively associated with deployment-related stressors and depression/anxiety during deployment, aPRs = 1.58-4.44. Associations remained robust after excluding responders with a history of mental health- and tobacco-related health encounters up to 3 years before deployment. Depression, anxiety, and tobacco initiation were cross-sectionally associated with oil spill response work experiences among DWH responders, who largely originated outside of the affected community., (© 2022 International Society for Traumatic Stress Studies.)