Giant papillary conjunctivitis (GPC) is usually a bilateral disease. However, in a small number of cases, GPC can be manifested as a unilateral, or a markedly asymmetrical disease in patients wearing bilateral contact lenses. We reviewed the clinical records of 148 patients with GPC to determine the incidence of unilateral GPC and its causative factors. Specifically, charts were reviewed for data on refractive error, keratometry, lens fit, lens care, lens replacement, and the presence or absence of associated ocular abnormalities (dry eyes, blepharitis, previous injury, or surgery). Fourteen patients with unilateral or markedly asymmetrical disease were identified. Overall, no statistically significant difference was found in lens care, refractive error, or keratometric measurements in the affected and unaffected eyes. While not statistically significant, infrequent lens replacement appears to be an important factor in the development of unilateral GPC. Three patients had a history of wearing an older lens in the GPC eye. Two patients were found with unilateral meibomian gland dysfunction involving the affected eye, and one patient had undergone surgery on the affected eye. No causative factor was identified in eight cases.