BACKGROUND: Posttraumatic stress disorder (PTSD) is a complex and debilitating anxiety disorder, and, although prolonged exposure therapy has been proven effective, many patients remain symptomatic after treatment. In other anxiety disorders, the supplementary use of D-cycloserine (DCS), a partial agonist at the glutamatergic N-methyl-D-aspartate receptor, showed promise in enhancing treatment effects. We examined whether augmentation of prolonged exposure therapy for PTSD with DCS enhances treatment efficacy. METHODS: In a randomized, double-blind, placebo-controlled trial we administered 50 mg DCS or placebo 1 hour before each exposure session to 67 mixed trauma patients, recruited from regular referrals, with a primary PTSD diagnosis satisfying DSM-IV criteria. RESULTS: Although DCS did not enhance overall treatment effects, the participants having received DCS did show a stronger treatment response. Exploratory session-by-session analyses revealed that DCS yielded higher symptom reduction in those participants that had more severe pretreatment PTSD and needed longer treatment. CONCLUSIONS: The present study found preliminary support for the augmentation of exposure therapy with DCS, specifically for patients with more severe PTSD needing longer treatment.