We have modeled a 3D structure for the C-type lectin domain of the African swine fever virus protein EP153R, based on the structure of CD69, CD94 and Ly49A cell receptors, and this model predicts that a dimer of EP153R may establish an asymmetric interaction with one MHC-I molecule. A functional consequence of this interaction could be the modulation of MHC-I expression. By using both transfection and virus infection experiments, we demonstrate here that EP153R inhibits MHC-I membrane expression, most probably by impairing the exocytosis process, without affecting the synthesis or glycosylation of MHC antigens. Interestingly, the EP153-mediated control of MHC requires the intact configuration of the lectin domain of the viral protein, and specifically the R133 residue. Interference of EP153R gene expression during virus infection and studies using virus recombinants with the EP153R gene deleted further support the inhibitory role of the viral lectin on the expression of MHC-I antigens.