Entamoeba histolytica (Eh) is an extracellular protozoan parasite of the human colon, which occasionally breaches the intestinal barrier. Eradicating ameba that invades is essential for host survival. A defining but uncharacterized feature of amebic invasion is direct contact between ameba and host cells. This event corresponds with a massive pro-inflammatory response. To date, pathogen recognition receptors (PRRs) that are activated by contact with viable Eh are unknown. Here we show that the innate immune system responds in a qualitatively different way to contact with viable Eh vs. soluble ligands produced by viable or dead ameba. This unique Eh Gal-lectin contact-dependent response in macrophages was mediated by activation of the inflammasome. Soluble native Gal-lectin did not induce inflammasome activation, but was sufficient for transcriptional priming of the inflammasome and non-inflammasome-dependent pro-inflammatory cytokine release. We conclude the inflammasome is a pathogenicity sensor for invasive Eh and identify for the first time a PRR that specifically responds to contact with intact parasites in a manner that accords with scale immune response to parasite invasion.