Post-traumatic stress disorder (PTSD) is a severe mental health disorder with limited treatment options. Gold standard treatment includes cognitive behavioral therapies (CBT) that incorporate exposure to traumatic memories to facilitate extinction. CBT can be effective in PTSD, but effects are incomplete and symptoms are prone to spontaneous return. Pharmacologically facilitating fear extinction could potentiate the effects of exposure-based therapy. Here, we explored whether targeting the endocannabinoid (eCB) system, a neuromodulatory system critically involved in fear extinction, would promote the efficacy of exposure-based CBT. Specifically, we tested the effects of elevating the eCB ligand anandamide (AEA) via inhibition of its main degradative enzyme, fatty acid amide hydrolase (FAAH). In this double-blind, placebo-controlled study, patients with PTSD (N = 100; 85 women) were randomized to the FAAH inhibitor (FAAHi) JNJ-42165279 (25 mg b.i.d.) or placebo for 12 weeks. In weeks 5-12, all participants completed an internet-delivered CBT that included exposure-based modules. The primary outcome was clinician-assessed PTSD symptom severity (CAPS-5). Secondary outcomes included self-reported symptoms of PTSD, depression, anxiety, and sleep quality. Blood samples were taken to measure levels of drug and eCBs. Overall, PTSD symptoms improved over time. While FAAHi increased AEA levels, there was no effect of FAAHi on PTSD symptoms or any secondary measure. FAAHi combined with internet-delivered CBT did not improve PTSD symptoms to a greater extent than internet-delivered CBT alone. Thus, FAAH inhibition does not appear to be a suitable adjunct treatment for enhancing CBT in PTSD. This study was registered as Eudra-CT 2020-001965-36.