Duck reovirus (DRV), a member of the genus Orthoreovirus in the family Reoviridae, was first isolated from Muscovy ducks. The disease associated with DRV causes great economic losses to the duck industry. However, the responses of duck (Cairna moschata) to the classical/novel DRV (C/NDRV) infections are largely unknown. To reveal the relationship of pathogenesis and immune response, the proteomes of duck spleen cells under the control and C/NDRV infections were compared. In total, 5986 proteins were identified, of which 5389 proteins were quantified. The different accumulated proteins (DAPs) under the C/NDRV infections showed displayed various biological functions and diverse subcellular localizations. The proteins related to the serine protease system were siginificantly changed, suggesting that the activated serine protease system may play an important role under the C/NDRV infections. Furthermore, the differences in the responses to the C/NRDV infections between the duck liver and spleen tissues were compared. Only a small number of common DAPs were identified in both liver and spleen tissues, suggesting diversified pattern involved in the responses to the C/NRDV infections. However, the changes in the proteins involved in the serine protease systems were similar in both liver and spleen cells. Our data may give a comprehensive resource for investigating the responses to C/NDRV infections in ducks. SIGNIFICANCE: A newly developed MS/MS-based method involving isotopomer labels and 'tandem mass' has been applied to protein accurate quantification in current years. However, no studies on the responses of duck (Cairna moschata) spleen tissue to the classical/novel DRV (C/NDRV) infections have been performed. As a continued study of our previous report on the responses of duck liver tissue to the C/NDRV infections, the current study further compared the differences in the responses to the C/NRDV infections between the duck liver and spleen tissues. Our results will provide an opportunity to reveal the relationship of pathogenesis and immune response and basic information on the pathogenicity of C/NDRV in ducks.