We successfully treated two patients with severe Staphylococcus epidermidis blepharoconjunctivitis by means of a topical vancomycin hydrochloride solution (50 mg/ml) prepared with sterile water. Aqueous vancomycin preparations, however, cause significant ocular irritation probably because of low pH and osmolality values. Solutions prepared with normal saline (5 mg/ml) and phosphate-buffered artificial tears (5 mg/ml and 50 mg/ml) were significantly less irritating and possessed equivalent in vitro antimicrobial activity. Topical vancomycin should be used only when commercially available antibiotics are inadequate.