BACKGROUND: The management of persistent physical symptoms poses a challenge in many healthcare settings, including primary care. Psychological treatments that involve exposure have shown promise for several conditions where patients suffer from persistent physical symptoms and unwanted responses to these. It is unclear, however, to what extent exposure therapy has effects beyond existing routine care interventions and who benefits the most. METHODS: A randomized controlled trial at a primary care center in Stockholm, Sweden compared 10 weeks of internet-delivered exposure therapy ( = 80) to healthy lifestyle promotion (HLP;  = 81) for patients bothered by at least one persistent physical symptom. The primary outcome was the mean reduction in subjective somatic symptom burden (Patient Health Questionnaire 15) as measured week-by-week up to the post-treatment assessment. Secondary outcomes included symptom preoccupation, anxiety, depression symptoms, and functional impairment. RESULTS: Patients contributed 1544 datapoints during treatment. The primary analysis showed no significant advantage of exposure therapy versus HLP in the reduction of mean somatic symptom burden ( = 0.14;  = 0.220). In secondary analyses, exposure showed superiority in the reduction of symptom preoccupation ( = 0.31;  = 0.033) but not anxiety, depression symptoms, or functional impairment. A higher somatic symptom burden or symptom preoccupation before treatment was predictive of a larger advantage of exposure versus HLP. CONCLUSIONS: Exposure therapy does not appear to show noteworthy average benefit over HLP, with the exception of symptom preoccupation. Substantial benefits are seen in patients with very high symptom burden or symptom preoccupation.