AIM: To investigate the risk factor of primary open angle glaucoma (POAG), which is the leading cause of irreversible blindness worldwide. An abnormally high level of endogenous formaldehyde (FA) has recently been found correlated with cell death and neurodegenerative disease, raising the possibility of a putative correlation of abnormal endogenous FA with POAG. METHODS: Thirty-four elderly patients with POAG and sixteen healthy controls were enrolled. Glaucomatous visual defects were present at both the functional (visual field) and structural [retinal nerve fiber layer (RNFL) thickness] levels. Morning urine samples were obtained and were analyzed by high-performance liquid chromatography (HPLC) to detect the endogenous FA level in a double blind manner. RESULTS: Patients with POAG (P<0.05) had significantly higher urine FA levels. The urine FA level of patients with severe visual field defects [mean deviation (MD)≥12 dB] was significantly (P<0.001) greater than that of patients with mild to moderate defects (MD<12 dB). By optical coherence tomography (OCT), the superior and inferior RNFL thickness of POAG group was significantly (P<0.001) thinner than in controls. Furthermore, the superior and inferior thinning of the RNFL was correlated with the elevation of urine FA concentration. CONCLUSION: Endogenous FA level is positively correlated with the neuronal defects of POAG.