Fragile X Syndrome (FXS) is one of the leading causes of mental retardation. In order to further investigate the role of phosphorylated ERK1/2 (p-ERK1/2) in abnormal behaviors in FXS, a series of behavioral experiments were used to compare anxiety-related responses and social interactions in Fmr1 knockout (KO) mice and wild type (WT) mice. In the open field test, velocity travel in the central area was increased in the KO mice compared with WT mice (P<0.01). Time mice spending in center was significantly decreased in KO mice (P<0.05). In the elevated plus maze test, the percentage of number of entrances was significantly decreased in open arm and increase in close arm (P<0.05) in KO mice compared with WT mice. In the three-chambered social approach test, KO mice exhibited significantly more approaches to the wire cup containing an acquaintance mouse than WT mice (P<0.05). Western blotting was used to detect ERK1/2 and p-ERK1/2 expression in hippocampal CA1 and CA3 region of Fmr1 KO mice and WT mice Expression of pERK1/2 of KO mice markedly increased in the hippocampal CA1 region compared with the WT group (P<0.05), while expression of ERK1/2 had no significant difference (P>0.05). The results show that ERK1/2 phosphorylation in the hippocampus is associated with abnormal anxiety-related and social behaviors in Fmr1 knockout mice. Altered ERK1/2 phosphorylation may play an important role in abnormal anxiety-related responses and social interactions in FXS patients. These findings suggest that ERK1/2 might be suitable as a new drug target for pharmacological treatment of FXS.