The effects of treatment of HeLa cells with the antitumor nucleoside analog 2'-deoxy-2'-(fluoromethylene) cytidine (FMdC) on ultraviolet and X-ray sensitivity were examined. A 1-h pretreatment with FMdC increased cellular sensitivity to both X-rays and ultraviolet irradiation as determined by survival curve analysis. Increased sensitivity to killing was accompanied by a clear reduction in the rate and extent of X-ray-induced DNA strand break repair and in the closure of excision repair-dependent DNA breaks following ultraviolet irradiation. These studies demonstrate that FMdC treatment compromises the repair of both ionizing ("short-patch") and nonionizing ("long-patch") DNA damage. The mechanism by which this is likely to occur is discussed. Based on these findings, it is likely that FMdC, in addition to possessing inherent antitumor activity, might provide additional antineoplastic benefit when administered in combination therapies with radiation.