The effect of zinc, nickel, cobalt and cadmium complexes of acyclovir (ACV) and its omicron-acetylated derivative (Ac-ACV) on the replication of wild type (wt) and ACV-resistant (ACV(R)) strains of Herpes simplex virus 1 (HSV-1) and Herpes simplex virus 2 (HSV-2) was examined. According to cytotoxicity, these compounds followed the order Ni-ACV chloride > Cd-ACV 3 Ni-ACV nitrate > ACV = Zn-ACV nitrate = Ac-ACV = Zn-Ac-ACV > Zn-ACV chloride > Co-ACV. Besides Ac-ACV, the only active complexes in inhibiting virus replication were Zn-ACV nitrate and Zn-Ac-ACV, which effectively suppressed the growth of both wt and ACVR strains of HSV-1 and HSV-2. The most active and most selective inhibitor of the growth of ACVR strains of HSV-1 and HSV-2 was Ac-ACV; its EC50 and SI were 100 and 10 times higher than those of ACV, respectively. Zn-Ac-ACV was less active than Ac-ACV, obviously due to the stability of the complex. Zn-ACV nitrate was active against both wt and ACVR strains of HSV-1; its activity and selectivity were 100 and 75 times higher than those of ACV, respectively. Ac-ACV and Zn-Ac-ACV suppressed the pre-mitotic arrest caused by HSV-1 infection during the first 2 hrs of infection and later on restored the cell division.