The earliest events following mucosal HIV-1 infection, prior to measurable viremia, remain poorly understood. Here, by detailed necropsy studies, we show that the virus can rapidly disseminate following mucosal SIV infection of rhesus monkeys and trigger components of the inflammasome, both at the site of inoculation and at early sites of distal virus spread. By 24 hr following inoculation, a proinflammatory signature that lacked antiviral restriction factors was observed in viral RNA-positive tissues. The early innate response included expression of NLRX1, which inhibits antiviral responses, and activation of the TGF-β pathway, which negatively regulates adaptive immune responses. These data suggest a model in which the virus triggers specific host mechanisms that suppress the generation of antiviral innate and adaptive immune responses in the first few days of infection, thus facilitating its own replication. These findings have important implications for the development of vaccines and other strategies to prevent infection. Display omitted •Following mucosal SIV infection of rhesus monkeys, the virus disseminates rapidly•The initial host response to the virus is mediated by components of the inflammasome•Early proinflammatory signature lacks expression of antiviral restriction factors•Host responses in the first few days after infection may facilitate SIV replication The initial host response against SIV infection suppresses the generation of effective antiviral innate and adaptive immune responses and may facilitate early-stage viral replication.