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We investigated the utility of a combination of autologous serum eye drops and a silicone–hydrogel (SH) lens in the treatment of persistent epithelial defects (PEDs).Eight patients who had distinct PED conditions were treated with 50% (v/v) autologous serum eye drops in combination with silicone hydrogel contact lenses and prospectively observed.The pathogenesis of PEDs included Sjo″gren-type dry eye syndrome, graft-versus-host disease, toxic keratitis, limbal cell deficiency, superior limbic keratoconjunctivitis, and neurotrophic keratitis. The patients had PEDs for 90±81.76 days (range: 30–240 days). Before the initiation of the combined treatment, three patients had already been unsuccessfully treated with SH lenses, and five patients had received serum eye drops alone. The PEDs of the eight eyes healed after a treatment period of 11.8±4.9 days. No visible deposits were noted on the surface of any contact lens.These findings demonstrate that the combination of an SH lens and serum eye drops may be effective in the treatment of intractable PEDs.