Poliovirus mutant 2A-1, which encodes a defective protease 2A, fails to inhibit translation of capped mRNAs selectively. Despite the failure of 2A-1 to inactivate cap-dependent translation, a reduction in the overall rate of protein synthesis, both virus and cell-specified, does occur after 2A-1 infection. This global reduction in protein synthesis is temporally correlated with an increase in [Na+]i and a decrease in [K+]i. The extensive global shutoff of protein synthesis is not observed in 2A-1 infected cells incubated in low NaCl medium or medium containing an elevated concentration of KCl which compensate for the virally-induced alterations in intracellular monovalent cation concentrations. Furthermore, 2A-1-specified protein synthesis is only partly resistant to hypertonic NaCl media which increase [Na+]i, in contrast to protein synthesis specified by wild-type poliovirus. These results suggest that shutoff of host and viral protein synthesis during infection by poliovirus mutant 2A-1 is a consequence of the virus-induced changes in intracellular monovalent cation concentrations.