5-(or 6-)Bromo-4,5-(or 5,7-)dichloro-1-beta-D-ribofuranosylbenzimidazole, 5,6-dibromo-1-beta-D-ribofuranosylbenzimidazole, and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole show closely similar structure-activity relationships with respect to inhibition of cellular RNA synthesis, cellular proliferation, and influenza virus multiplication, and also with respect to enhancement of interferon production. The activities ofth ese compounds are ranked 20:2.5:1. The log dose-response curves constructed for inhibiton of FS-4 cell RNA synthesis show similar slopes and a leveling off at 60-70% inhibition of RNA synthesis at the highest concentrations of each compound tested. This evidence suggests that these three derivatives act through the same mechanism. It has been shown previously that the dichloro compound selectively inhibits nuclear heterogenous RNA and messenger RNA synthesis. The concentrations of the benzimidazole ribosides at which the rate of proliferation of human fibroblasts (FS-4) is reduced by 50% are as follows: monobromodichloro: 1.7 muM (0.68 mug/ml); dibromo: 12 muM (4.9 mug/ml); dichloro: 38 muM (12 mug/ml). All compounds reduce the exponential rate of cell proliferation in a dose-dependent manner. The inhibition of cell growth is reversible upon removal of the compounds from the medium. Protocols based on any one of the three halobenzimidazole ribosides give interferon yields from poly(I)-poly(C)-induced FS-4 cells which are comparable to the high yields obtained with the conventional cycloheximide-actinomycin D protocol. The enhancement of interferon yield depends on blocking of the synthesis of RNA which is involved in the shutoff of interferon production.