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ImportanceFew evidence-based treatments are available for Gulf War illness (GWI). Behavioral treatments that target factors known to maintain the disability from GWI, such as problem-solving impairment, may be beneficial. Problem-solving treatment (PST) targets problem-solving impairment and is an evidence-based treatment for other conditions.ObjectiveTo examine the efficacy of PST to reduce disability, problem-solving impairment, and physical symptoms in GWI.Design, Setting, and ParticipantsThis multicenter randomized clinical trial conducted in the US Department of Veterans Affairs compared PST with health education in a volunteer sample of 511 Gulf War veterans with GWI and disability (January 1, 2015, to September 1, 2019); outcomes were assessed at 12 weeks and 6 months. Statistical analysis was conducted between January 1, 2019, and December 31, 2020.InterventionsProblem-solving treatment taught skills to improve problem-solving. Health education provided didactic health information. Both were delivered by telephone weekly for 12 weeks.Main Outcomes and MeasuresThe primary outcome was reduction from baseline to 12 weeks in self-report of disability (World Health Organization Disability Assessment Schedule). Secondary outcomes were reductions in self-report of problem-solving impairment and objective problem-solving. Exploratory outcomes were reductions in pain, pain disability, and fatigue.ResultsA total of 268 veterans (mean [SD] age, 52.9 [7.3] years; 88.4% male; 66.8% White) were randomized to PST (n = 135) or health education (n = 133). Most participants completed all 12 sessions of PST (114 of 135 [84.4%]) and health education (120 of 133 [90.2%]). No difference was found between groups in reductions in disability at the end of treatment. Results suggested that PST reduced problem-solving impairment (moderate effect, 0.42; P = .01) and disability at 6 months (moderate effect, 0.39; P = .06) compared with health education.Conclusions and RelevanceIn this randomized clinical trial of the efficacy of PST for GWI, no difference was found between groups in reduction in disability at 12 weeks. Problem-solving treatment had high adherence and reduced problem-solving impairment and potentially reduced disability at 6 months compared with health education. These findings should be confirmed in future studies.Trial RegistrationClinicalTrials.gov Identifier: NCT02161133