Obsessive compulsive disorder (OCD) is a severe illness that affects 2-3% of people worldwide. OCD neuroimaging studies have consistently shown abnormal activity in brain regions involved in decision-making (orbitofrontal cortex [OFC]) and action selection (striatum). However, little is known regarding molecular changes that may contribute to abnormal function. We therefore examined expression of synaptic genes in post-mortem human brain samples of these regions from eight pairs of unaffected comparison and OCD subjects. Total grey matter tissue samples were obtained from medial OFC (BA11), lateral OFC (BA47), head of caudate, and nucleus accumbens (NAc). Quantitative polymerase chain reaction (qPCR) was then performed on a panel of transcripts encoding proteins related to excitatory synaptic structure, excitatory synaptic receptors/transporters, and GABA synapses. Relative to unaffected comparison subjects, OCD subjects had significantly lower levels of several transcripts related to excitatory signaling in both cortical and striatal regions. However, a majority of transcripts encoding excitatory synaptic proteins were lower in OFC but not significantly different in striatum of OCD subjects. Composite transcript level measures supported these findings by revealing that reductions in transcripts encoding excitatory synaptic structure proteins and excitatory synaptic receptors/transporters occurred primarily in OFC of OCD subjects. In contrast, transcripts associated with inhibitory synaptic neurotransmission showed minor differences between groups. The observed lower levels of multiple glutamatergic transcripts across both medial and lateral OFC may suggest an upstream causal event. Together, these data provide the first evidence of molecular abnormalities in brain regions consistently implicated in OCD human imaging studies.