Human IL-10 (hIL-10) signaling is mediated by receptors consisting of two subunits, IL-10 receptor 1 (IL-10R1) and IL-10 receptor 2. Two common variants of the IL-10R1 (Ser 138 Gly (single-nucleotide polymorphism 3, SNP3) and Gly 330 Arg (SNP4)) are associated with diverse disease phenotypes. Viral homologs to hIL-10, such as cmvIL-10, utilize the same IL-10 receptor complex as part of viral immune evasion strategies. For the present study we hypothesized that IL-10R1 variants alter the ability of viral IL-10 to utilize the IL-10R1 signaling pathway. HeLa cell clones expressing different IL-10R1 haplotypes (WT or any variant) were incubated with hIL-10 or cmvIL-10. In cells expressing IL-10R1-WT, cmvIL-10 (both non-glycosylated- and HeLa-expressed) resulted in equal or slightly stronger STAT3 phosphorylation compared with hIL-10. In clones expressing IL-10R1-SNP3, IL-10R1-SNP4 or IL-10R1-SNP3+4, the cmvIL-10 showed significantly less STAT3 phosphorylation, especially when HeLa-expressed cytokines were used. Time course experiments demonstrated a slower kinetic of cmvIL-10 STAT3 activation through the variant IL-10R1. Similarly, IL-10R1 variants decreased the cmvIL-10-induced SOCS3 and signaling lymphocytic activation molecule mRNA expression. These data suggest that the IL-10R1 variants differentially reduce the signaling activity of cmvIL-10 and thereby may affect CMV's ability to escape from the host's immune surveillance.