Human rhinovirus type 2 did not replicate in nonpermissive mouse cells; the restriction was not in adsorption but in the early events of virus replication. Mutants which had been adapted to grow in mouse cells had the following characteristics: (i) no change in the structural protein, (ii) a larger nonstructural protein and its precursor protein, and (iii) an altered viral RNA synthesis. The altered nonstructural proteins correlated with a change in host range of the virus and may be involved in viral RNA synthesis.