Spontaneous fetal loss is associated with herpes simplex virus (HSV) infection as deduced from epidemiologic data. To date, the underlying mechanisms remain to be elucidated, but an immune component is suspected. HLA-G is a class I MHC molecule selectively expressed on extravillous cytotrophoblast; this cell type does not express conventional HLA-A or -B, whereas expression of novel HLA-C-like products has been reported. While its function remains unclear, a role for HLA-G in silencing NK cells that would otherwise attack cells devoid of classical class I molecules has been invoked. We here show that expression of HLA class I molecules is abrogated in HSV-infected choriocarcinoma cells, a phenomenon mediated by the virally encoded inhibitor of the transporter associated with Ag presentation, ICP47. These observations may provide a link between HSV infection and spontaneous fetal loss.