Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and liver/lymph node-specific intercellular adhesion molecules-3-grabbing non-integrin (L-SIGN) are calcium-dependent C-type lectin receptors (CLRs). Both proteins mediate the entrance of viruses by recognizing mannose or fructose oligosaccharides on the viral surface. However, potential regulation of DC-SIGN or L-SIGN on viral replication is neglected. In this study, we established murine cell lines stably expressing DC-SIGN, L-SIGN and their functional domain chimeras respectively, and analyzed the impacts of the expressed proteins on murine coronavirus replication. The results showed that L-SIGN had a more obviously inhibitory effect on viral replication than DC-SIGN, which was related to difference in the sequences. The inhibitory effect might act by antagonizing the downregulation of extracellular signal-regulated kinase (ERK) signaling pathway triggered by the virus. DC-SIGN was not found to directly mediate the entry of virus into receptor-unexpressed cell lines. The regulation of DC-SIGN and L-SIGN on the viral replication was dependent on the viral receptor mouse carcinoembryonic antigen-related cell adhesion molecule 1a (mCEACAM1a) which might interact with DC-SIGN trimer on the cell surface. These results suggest that CLR can regulate the viral replication through interference with signaling events even if they cannot mediate directly the entry of the virus.