A series of acyclic phosphonomethylether nucleosides were synthesized and then evaluated for inhibitory activity against respiratory viruses of clinical significance using CPE inhibition, neutral red uptake and virus yield reduction assays. Of the 20 compounds synthesized, none significantly inhibited influenza A or B viruses or respiratory syncytial virus strains A2, Long or 18537; the selective indices (SI) were less than 10. A new compound, GS-2128 (2R, 5R-9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]adenine; D4API), selectively inhibited adenovirus 5 (SI>10) as did GS-0577 (9-(3-hydroxy-2-phosphonylmethoxypropyl)-adenine; HPMPA) and GS-0504 [(S)-1-[3-hydroxy-2-(phosphonylmethoxypropyl)]-cytosine; HPMPC]. The 50% effective concentrations (EC50) ranged from 8-100 μg mL-1 and 50% cell inhibitory concentrations (CC50) from 40-1000 μg mL-1. All three compounds were also found to be active against laboratory strains and clinical isolates of adenovirus types 1, 2, 8 and 41 with EC50 values ranging from 0.2 to 10 μg mL-1. Two compounds, GS-438 (9-(2-phosphonylmethoxyethyl)guanine, PMEG) and GS-2542 (9-[3-phosphonomethoxy)methoxymethyl]guanine) inhibited parainfluenza virus 3 strain C243, with SI of 52 and >333, respectively, PMEG also inhibited measles virus strains CC, Halonen and Chicago with EC50 values ranging from 0.03-9 μg mL-1. These data suggest that these compounds should be considered for possible development as therapeutic agents for respiratory virus infections.