Interactions of western equine encephalomyelitis (WEE) virus are compared with mesenterons of 2 genetically selected susceptible (WS) and refractory (WR) lines of Culex tarsalis. Both WS and WR females had similar susceptibility when parenterally inoculated with virus, thus it was initially thought that resistance in WR Cx. tarsalis was associated with a mesenteronal infection barrier. Present data on viral growth in mesenterons dissected from females fed on virus-soaked pledgets suggest that virus infected and multiplied in some WR mesenterons, but to significantly lower titers than in WS mesenterons. The proportion of WR females with infected mesenterons varied depending on the time after feeding, incubation temperature, and whether mesenterons were incubated with WEE viral antibody before viral assay. The percentage of WR mesenterons infected did not increase significantly when diethylaminoethyl dextran was added to the infectious bloodmeal, the pH of the infectious bloodmeal was altered, or virus was introduced by intrathoracic inoculation into the hemocoel. It was concluded that the low titers of virus detected in both WR mesenterons and whole mosquitoes were influenced by the genetic ability of WR Cx. tarsalis to modulate WEE viral titers to low or undetectable levels after peroral or parenteral infection. These findings make it difficult to determine what proportion of the WR mesenterons are resistant to infection with WEE virus. WS and WR Cx. tarsalis were equally susceptible to peroral infection with the flavivirus St. Louis encephalitis and the bunyavirus Turlock.