Objective： To investigate the protective effect of histone deacetylase inhibitor NL101 on Lhomocysteine (HCA)induced toxicity in rat neurons, and the toxic effect on normal rat neurons. Methods： In the presence of NL101 at various concentrations, HCA (5 mmol/L)induced changes in cell density, necrosis, and viability were determined in the mixed cultures of rat cortical cells and the primary cultures of rat neurons. The direct effect of NL101 on primary neurons was also observed in the absence of HCA. Histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) was used as the control. After the treatments, cell viability, the density, and morphology of neurons and glial cells, and cell necrosis were determined. Results： In the mixed cultures of cortical cells, NL101 had no effect on HCA (5 mmol/L)induced cell number reduction at 0.00110  μmol/L; however, it significantly attenuated necrosis at 110  μmol/L, and increased neuronal number at 1  μmol/L. NL101 had no effect on the mixed cortical cells in the absence of HCA. In the primary neurons, NL101 reduced neuronal viability and mildly increased necrosis at 110  μmol/L in the absence of HCA, while it significantly attenuated HCAinduced neuronal viability reduction at 0.0110  μmol/L and reduced neuronal necrosis at 110  μmol/L. The effects of NL101 were apparently similar to those of SAHA. Conclusion： NL101 has protective effect on HCAinduced neuronal injury but it is neurotoxic at high concentrations, which is similar to the typical histone deacetylase inhibitor SAHA.