Upon serial passage of BHK-21 cells persistently infected with foot-and-mouth disease virus (FMDV) C-S8c1, cells with increased resistance to the virus were selected (J. C. de la Torre, E. Martinez-Salas, J. Diez, and E. Domingo, J. Virol. 63:59-63, 1989). Two highly resistant cell clones, 74A11 and 74D12, were transformed to puromycin resistance (Purr) and were fused to BHK-21 cells transformed to neomycin resistance (Neor). The hybrid Neor Purr cells showed the specific resistance to FMDV C-S8c1 characteristic of clones 74A11 and 74D12. The results suggest that resistance to FMDV C-S8c1 is mediated by trans-acting cellular products. The possibility of engineering constitutive resistance to FMDV is discussed.