Availability of nicotinic acetylcholine receptors containing β2 subunits (β2-nAChRs) was studied in unmedicated, symptomatic patients with post-traumatic stress disorder (PTSD) and healthy control subjects, all current non-smokers. A subgroup of participants had a history of smoking. Availability of β2-nAChRs in the mesiotemporal cortex, prefrontal cortex, thalamus and striatum was determined using the radiotracer [123I]5-IA-85380 ([123I]5-IA) and single-photon emission computed tomography (SPECT). PTSD symptoms were assessed using the Clinician-Administered PTSD Scale (CAPS). Never-smoking PTSD patients compared to never-smoking healthy controls showed significantly higher [123I]5-IA binding in the mesiotemporal cortex (ANOVA: F=6.21, d.f.=1, 11, p=0.030). Among all PTSD patients, there was a significant correlation between the re-experiencing symptom cluster and thalamic [123I]5-IA binding (R2=0.66, p=0.019, Bonferroni corrected). These findings not only suggest an involvement of β2-nAChRs in the pathophysiology of PTSD but also raise the possibility that this receptor may be a novel molecular target for drug development.