As part of a project to identify genes up-regulated by injury of the motor neuron, a clone encoding dimethylarginine dimethylaminohydrolase (DDAH) was isolated. This enzyme is known to metabolize methylarginines, which are endogenous inhibitors of NOS activity. DDAH may therefore contribute to the control of NO synthesis. The present study demonstrated that both DDAH and nNOS mRNAs are up-regulated after axotomy in injured hypoglossal motor neurons. The profile of DDAH mRNA up-regulation in the injured hypoglossal motor neurons paralleled that of NADPH diaphorase staining. While the expression of both DDAH and nNOS was upregulated in motor neurons following nerve injury, the normal distribution of DDAH and nNOS mRNAs in the noninjured central nervous system were distinctly different. We speculate that both genes are involved in the upregulation of NO production following nerve transection, although the role of NO in the process of nerve regeneration is so far unknown.