Currently, acetylcholinesterase (AChE) inhibitors, such as donepezil, are considered the main therapeutic agents for Alzheimer's disease (AD). It has been suggested that AChE inhibitors have other pharmacological effects including nicotine receptor stimulation and neuroprotection. We reported previously that treating AD with rivastigmine (Riv) enhanced nerve growth factor (NGF)-induced neurite outgrowth; in the present study, we investigated the mechanism underlying this enhancement. PC12 cells were treated with NGF (50 ng/mL) alone or with NGF and Riv (0-100 µM); the neurite length of the cells was measured 24 h after incubation. Physostigmine (100 µM) was used as a control. Using the same method, we investigated neurite outgrowth when the sigma receptor was knockdown by siRNA. The neurite outgrowth effect of NGF was enhanced by Riv in a concentration-dependent manner but not by physostigmine. Further, potentiation by Riv was not inhibited by the combination of scopolamine or hexamethonium. However, both the sigma-1 receptor blocker NE-100 and the sigma-2 receptor blocker SM-21 reduced the effects of Riv by approximately 50%. Furthermore, when NE-100 and SM-21 were used in combination, the effects of Riv disappeared. Similarly, knockdown of sigma-1 and sigma-2 receptors by siRNA abolished the effects of Riv. These results demonstrate that rivastigmine exhibits an NGF-enhancing effect via the sigma receptor, regardless of the AChE inhibitory effect.