Calcium channel blockers reduce Ca++ flux through membrane channels and may inhibit intracellular Ca++-dependent synthetic and regulatory activities by binding to calmodulin. We have found that Verapamil, a calcium channel blocker, inhibits influenza virus replication in Madin-Darby canine kidney cells and in murine pulmonary macrophages and that this antiviral effect occurs with drug addition late in the replication cycle. Chlorpromazine, a drug which binds to calmodulin, also inhibited influenza virus replication in these tissue culture systems. We suggest that Verapamil and chlorpromazine inhibit influenza virus replication by interfering with calmodulin-dependent intracellular activities necessary for late synthetic steps or virus assembly steps and that calcium channel blockers provide a new probe for investigating influenza virus replication.