The oligodendrocyte lineage gene (Olig1) was first identified in screens, and was shown to be a master regulator during differentiation of oligodendrocyte precursors into myelin forming oligodendrocytes. Olig1 was also shown to be required for myelin repair during multiple sclerosis. While co-regulator proteins for nuclear Olig1 are well established, co-regulator proteins for cytoplasmic Olig1 remain unknown. Using a yeast two-hybrid strategy, we found that Olig1 bound to a human homologue of the Arabidopsis COP9 signalosome subunit 7a (COPS7A). Moreover, the interaction between Olig1 and COPS7A was subsequently confirmed by both in vitro and in vivo co-immunoprecipitation assays and immunofluorescent staining. In particular, confocal laser microscopic images showed that Olig1 and COPS7A co-localized to the cytoplasm of oligodendrocytes in the adult rat corpus callosum. By contrast, COPS7A was consistently expressed in oligodendrocyte lineage cells, and was down-regulated during the peak period of myelination. Collectively, these findings suggested that COPS7A associated physically with Olig1, and it might thus serve as a novel negative regulator in oligodendrocytes differentiation.