AbstractBackground and aimsPost‐traumatic stress disorder (PTSD) and substance use disorder (SUD) are highly co‐occurring and evidence for the optimal ways of treating PTSD in SUD patients is mixed. Our aim was to compare three different PTSD treatments, each added simultaneously to SUD treatment, with SUD treatment alone in patients with co‐occurring SUD‐PTSD. These PTSD treatments were: Prolonged Exposure (PE), Eye Movement Desensitization and Reprocessing (EMDR) and Imagery Rescripting (ImRs).DesignA single‐blind 4‐arm randomized controlled trial with follow‐up at 3 months.SettingTwo addiction treatment centers in the Netherlands, providing intra‐ and extramural care.Participants209 patients with SUD and co‐morbid PTSD were included [mean age 37.5 (standard deviation, SD = 11.99), female sex = 46.4%, mean Clinically Administered PTSD Scale (CAPS) score = 37.35 (SD = 9.28)].InterventionsParticipants were randomized to either simultaneous SUD + PE (n = 53), SUD + EMDR (n = 50), SUD + ImRs (n = 55) or to SUD treatment only (n = 51), with the active PTSD treatments consisting of 12 sessions each within 3 months. Standard protocols were used.MeasurementsThe primary outcome was clinician‐administered PTSD symptom severity as measured by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (CAPS‐5) at 3 month follow‐up. Secondary outcomes included loss of PTSD diagnosis, full remission of PSTD and SUD‐severity, also recorded at 3 months.FindingsCompared with SUD only, the mean differences in CAPS‐5 score were B = −5.41 [95% confidence interval (CI) = 10.88, 0.05, P = 0.052] for SUD + PE, B = −7.97 (95% CI = −13.57, −2.37, P = 0.006) for SUD + EMDR and B = −10.03 (95% CI = −15.29, −4.77, P < 0.001) for SUD + ImRs. When adjusted for baseline covariates, mean differences were B = −5.81 (95% CI = −11.48, −0.15, P = 0.044) for SUD + PE, B = ‐8.85 (95% CI = −14.60, −3.10, P = 0.003) for SUD + EMDR and B = ‐10.75 (95% CI = −15.94, −5.56, P = <0.001) for SUD + ImRs. No between‐group differences in SUD outcomes were found.ConclusionsAmong people with co‐occurring substance use disorder (SUD) and post‐traumatic stress disorder (PTSD), trauma‐focused PTSD treatment as add‐on to SUD treatment appears to be effective in decreasing PTSD severity compared with manualized SUD only treatment and does not appear to increase SUD severity.