To become potent T-cell stimulators, DCs need to mature. Treatment with soluble CD83 (sCD83) induces immune tolerance and protects against transplant rejection by maintaining dendritic cells in an immature, tolerogenic state. Until now, the mechanism through which sCD83 keeps DCs immature has not been investigated. The internalizing pathway of CD83 was screened by Western blot, and the direct interactions between internalized proteins were verified through coimmunoprecipitation (co-IP) and transmission electron microscopy (TEM). CD83 plasma membrane levels were detected by Western blot using a plasma membrane protein extraction protocol. The changes in CD83 surface levels in DCs were detected by flow cytometry. Caveolin-1 function was detected in a kidney transplant model. In this study, we demonstrated that caveolin-1 could affect CD83 level during endocytosis in mouse DCs. Caveolin-1 coprecipitates with CD83, as demonstrated by co-IP analysis. TEM morphometric analysis of the entire CD83 distribution associated with internalized caveolin-1 demonstrated a significant interaction in cellular vesicles. sCD83 reduces endogenous CD83 plasma membrane levels, and caveolin-1 knockdown reverts CD83 levels in plasma membrane. sCD83 treatment decreases CD83 surface levels in DCs. siRNA to caveolin-1 in DCs inhibits this effect of sCD83. The effects of sCD83-treated DCs were proved in CD1 mice. Knocking down caveolin-1 in DCs obstructs the effects of sCD83 on kidney transplant. In conclusion, our data indicated that a caveolin-dependent endocytic pathway is involved in CD83 internalization in DCs and that caveolin-1 is involved in the activity of DCs.