Infections caused by cytomegalovirus (CMV) resistant in vitro to ganciclovir, defined as requiring greater than 6 mumols of ganciclovir for ED50 have developed in some AIDS patients with progressive CMV retinitis despite chronic ganciclovir therapy. Two such patients (CMV isolates ED50, 9.5-14.5 mumols) were treated with foscarnet, an antiviral pyrophosphate analogue to which both patients' isolates demonstrated in vitro susceptibility (ED50, less than or equal to 300 mumols). Each patient had documented retinitis progression, at 2- and 1- to 5-week intervals, respectively, despite high-dose intravenous ganciclovir therapy. Both patients responded to foscarnet therapy with cessation of viral shedding in urine and blood. After foscarnet therapy was started, retinitis stabilized in the two patients for 12 and 25 weeks, respectively, before progression recurred. Therefore, foscarnet may be effective in immunocompromised patients with rapidly progressive CMV retinitis whose CMV isolates have developed in vitro resistance to ganciclovir.