AIM: To compare the effectiveness between multiple intravitreal injections of ganciclovir alone and combined with foscarnet as initial treatment for patients with newly-onset cytomegalovirus retinitis (CMVR). METHODS: The retrospective study observed 37 patients (58 eyes) who suffered from CMVR onset between 2013 and 2015. Among them, 35 eyes underwent 4 weekly intravitreal injections of 3.0 mg ganciclovir, and 23 eyes underwent 4 weekly injections of 3.0 mg ganciclovir combined with 2.4 mg foscarnet. Visual acuity, intraocular pressure and viral load of cytomegalovirus (CMV) in aqueous humor measured by real-time polymerase chain reaction were compared before and after each injection. RESULTS: CMV-DNA copies in aqueous humor decreased remarkably in both groups. The average of CMV-DNA copies in patients’ aqueous decreased from 38.3×104 copies/mL at baseline to 2.2×104 copies/mL after the 4th injection in patients who were treated with ganciclovir monotherapy, and decreased from 76.9×104 copies/mL to 11.3×104 copies/mL after 4 continuous injections of ganciclovir combined with foscarnet. No significant difference was found in reduction of viral load, change of visual acuities or intraocular pressures between monotherapy or combined therapy. CONCLUSION: Results of this study show that the initial effectiveness of treating CMVR after 4 weekly intravitreal injections is not significantly different from ganciclovir alone or combined with foscarnet. Continuous injection of ganciclovir alone is sufficient in treating immunosuppressive patients with newly-onset CMVR.