Both lidocaine (LIDO) and the calmodulin (CaM) antagonists, pimozide (PIM) and trifluoperazine (TFP), enhanced bleomycin (BLM) induced cytotoxicity and DNA damage. The toxicity with the combination of BLM and CaM antagonists represented true pharmacological synergism and was observed with the addition of the CaM antagonist either during or after BLM exposure. Additionally, the DNA damage of BLM and the BLM-like drugs, talisomycin S10b (TAL) or peplomycin (PEPLO), was also enhanced by CaM antagonists. LIDO, which similarly increased the lethal effects and DNA damage of BLM in L1210 cells, was also effective only during or after BLM exposure. The data presented here indicate that the modulation of toxicity seen with these drug combinations is reflected by changes in DNA integrity. Furthermore, these data suggest that the inhibition of DNA repair processes may be at least partially responsible for the enhanced toxicity and DNA damage when CaM antagonists or LIDO are added to BLM.