BACKGROUND: Although mindfulness-based interventions (MBIs) are widely used in clinical and nonclinical settings, there has been little systematic study of their potential risks. To address this gap, we examined differences in psychological and physical worsening among participants in the usual care and intervention conditions of a 3-group, randomized pragmatic trial (Learning to Apply Mindfulness to Pain [LAMP]) that tested the effectiveness of 2 approaches to delivering MBIs to patients with chronic pain. METHODS: The sample consisted of 374 male and 334 female patients with chronic pain enrolled in the LAMP trial who completed a 10-week follow-up survey, 61% of whom had a mental health diagnosis. Psychological and physical worsening was assessed by a checklist asking whether participants experienced specific symptoms since beginning the study. We used multivariable logistic regression models with imputed data to determine whether predicted probabilities of increased symptoms differed between usual care and the 2 MBIs. RESULTS: Participants in usual care were more likely to report experiencing increased psychological and physical worsening than were those in the MBIs, including an increase in disturbing memories; sadness, anxiousness, and fatigue; isolation and loneliness; and feeling more upset than usual when something reminded them of the past. CONCLUSIONS: MBIs do not appear to cause harm, in terms of increased symptoms, for this population of patients with chronic pain and high levels of mental health comorbidities. CLINICAL TRIAL REGISTRATION: Preregistration with an analysis plan at www.ClinicalTrials.gov: NCT04526158. Patient enrollment began December 4, 2020.