Objective To detect the expression of DDX3 and casein kinase 1ε(CK1ε) in the hippocampus of the amyotrophic lateral sclerosis (ALS) transgenic mice, and to explore the relationship between the expression of DDX3 or CK1ε and the pathogenesis of ALS. Methods Thirty-three wild ALS transgenic mice and thirty-three wild-type mice were killed at different stages. The expressions of DDX3 and CK1ε were detected by RT-PCR and Western blotting. The distribution of DDX3 and CK1ε positive cells in the hippocampus and the coexpression of DDX3 or CK1ε with astrocytes or neurons in the hippocampus were detected by a double immunofluorescence technology. Results DDX3 mRNA and protein in the hippocampus of ALS mice were of no significant differences at the early stage, but decreased at the middle and end stages, compared with wild-type mice. CK1ε mRNA and protein were all decreased at the three different stages, compared with the wild-type mice. Double immunofluorescence result showed that DDX3 and CK1ε positive cells were co-localized in the district demtate gyrusc(DG) and CA of the hippocampus. DDX3 and CK1ε mainly expressed in neurons, not in astrocytes. Compared with the wild-type mice, the immunoreactivity of DDX3 and CK1ε in the hippocampus of ALS mice decreased obviously. Conclusion The expression of both DDX3 and CK1ε mRNA and protein decrease in the hippocampus of ALS mice, compared with the wild-type mice, indicating that the abnormal expression of DDX3 and CK1ε is closely related to hippocampus lesion in ALS.