To determine whether reduced nerve growth factor (NGF) and/or its high affinity receptor, trkA, play a role in the pathophysiology of Rett syndrome (RS), we used immunohistochemistry in paraffin-embedded human autopsy brain tissue, to quantify NGF and trkA levels within the frontal cortex of 9 RS females and 10 female controls of similar age. The results showed a significant reduction of NGF expression in RS patients (p < 0.001). Specifically, all RS brains exhibited NGF levels at or below the minimum level observed in controls. In 3 RS brains there was no NGF detected. TrkA expression was also reduced in the RS group (p = 0.035). Interestingly, the expression of NGF in the RS group was significantly related to the presence of cortical astrogliosis (r = 0.91) as indicated by immunostaining for glial fibrillary acidic protein (GFAP). This suggests that while the signals for NGF production during injury remain intact, the critical developmental signals required for early NGF production are impaired.