Microbial keratitis (MK) is a serious complication associated with contact lens wear. In this case series we report three clinical presentations of MK associated with daily-wear monthly-replacement soft contact lenses. All of these patients were using vifilcon A (55% water content, ionic, U.S. Food and Drug Administration [FDA] group IV) monthly-replacement soft contact lenses. A gram-stained smear of the corneal scrapings of two patients showed numerous gram-negative cocci bacilli, and tissue cultures showed significant growth of Pseudomonas aeruginosa. In the third patient, the corneal scrapings showed numerous gram-negative bacilli, along with gram-positive cocci, and tissue culture showed significant growth of Aeromonas species and alpha-hemolytic streptococci. All these cases were resolved by medical therapy. This case series highlights the importance of patient symptoms, clinical features, and microbiologic work-up in making a differentiation between MK and sterile contact lens-induced peripheral ulcer (CLPU). A high index of suspicion and close follow-up care will avoid misdiagnosis and reduce complications.