We investigated the early innate immune responses induced in human intestinal epithelial cells (IEC) by the three defined Toxoplasma gondii genotype strains. Transcriptome analysis revealed that among differentially expressed genes, beta-defensins distinguished the most IEC infected by fast- or slow-replicating T. gondii genotypes. Although beta-defensin 1 and 3 genes were not expressed in host cells at early time points postinfection, the slow-replicating type II and III parasites induced high levels of beta-defensin 2 gene expression. Notably, no beta-defensin 2 gene expression occurred early after infection with the fast-replicating type I parasite. However, activation of this gene in IEC by poly(I:C) treatment prior to infection substantially decreased parasite viability, and pretreatment of parasites with synthetic beta-defensin 2 significantly reduced their infectivity of IEC. These findings strongly support the modulation of early beta-defensin 2 expression as a mechanism used by type I T. gondii parasites to mediate immune evasion