When Culicoides variipennis (Coquillett) ingested a bluetongue virus (BTV)-defibrinated sheep blood suspension, BTV adsorbed to sheep red blood cells (RBCs) within 2 h. The virus had entered RBCs by 6 h and was still seen in RBCs 2 d after ingestion of the blood meal, even though the RBCs had been dehydrated. The peritrophic membrane began to form on day 1, and it contained breaks by day 3. The peritrophic membrane did not prevent infection of the midgut epithelium. Viral replication occurred in the midgut cells; virions matured through the basolateral extracellular membrane into the extracellular spaces between the plasma membrane and the basal lamina. The greatest number of virions was seen on day 3. The virus did not accumulate but rather exited the cells when mature. No cytopathology was observed in virus-infected cells, and midgut cells became vacuolated and sloughed off into the midgut lumen by day 3 in both control and virus-infected cells.