There have been numerous reports regarding the occurrence of keratitis in patients with soft contact lenses, but few reports in patients with rigid gas permeable contact lenses. To the best of our knowledge, the occurrence of infection associated with three species of pathogens has never been reported. Here, we describe a patient who exhibited refractory painless keratitis caused by three pathogens (Staphylococcus epidermidis, Acanthamoeba, and herpes simplex virus) and summarize similar reports published at multiple centers worldwide, with the aim of providing guidance for clinicians who might encounter mixed-type corneal infections. We describe the results of many ophthalmologic and laboratory investigations, which guided our treatment selection. We achieved good treatment efficacy, such that the patient exhibited a corrected visual acuity of 20/20 in the affected eye after a series of treatments, including curettage of ulcer lesions. Corneal infections caused by multiple pathogens are challenging in clinical practice. This summary of our experience in patient diagnosis and treatment can help clinicians to achieve a favorable prognosis in treatment of future patients.