Glutamatergic dysfunction is implicated in the pathophysiology of fragile X syndrome (FXS). The purpose of this pilot study was to examine the effectiveness and tolerability of memantine for a number of target symptoms associated with FXS. Medical records describing open-label treatment with memantine in 6 patients with FXS and a comorbid diagnosis of PDD were reviewed. Six patients received memantine over a mean 34.7 weeks of treatment. Four of 6 (67%) patients showed global clinical benefit on ratings with the CGI-I. Symptom specific rating scales, however, showed no statistically significant improvement. Two patient developed treatment-limiting irritability on memantine. Memantine was modestly effective in several patients with FXS. Further systematic study is warranted.