A series of 2'-deoxy-2'-fluororibosides were evaluated for anti-influenza activity in cell culture and in the mouse pneumonia model. Many were found to be potent inhibitors of Influenza A, in chick embryo fibroblast cells (IC50's 0.1-2.9 muM), and in reducing mouse lung virus litres (1-3 log10 units). Purine analogues proved the most effective, but their activity was an order of magnitude higher in MDCK cells. Anti-influenza activity correlated with intracellular triphosphate levels and with substrate specificity of 2'-deoxycytidine kinase. 2'-deoxy-2'-fluoroguanosine selected for further study was active against all influenza A and B strains tested, including one clinical isolate which proved extremely sensitive when assayed in human tracheal cultures. In vivo, 2'-deoxy-2'-fluoroguanosine (2'-fluorodGuo) was significantly more effective than amantadine or ribavirin in reducing mouse lung virus titre when treatment commenced after infection.