Oral contraceptive (OC) use has been associated with increased incidence of a number of infections, but the mechanisms behind these changes is unclear. The present study compared OC users and nonusers in natural killer (NK) cell activity, NK phenotype, and illness frequency. Subjects were 55 female medical students (19 OC users, 36 nonusers). Three blood samples were obtained, 1 mo apart. Natural cytotoxicity was tested with a 51Cr assay. Self reports of illness symptoms during the previous week were collected at each blood sampling. NK phenotype number was assessed by flow cytometry. Oral contraceptive users had lower natural cytotoxicity and increased frequency of sneezing, gastrointestinal distress, runny nose, sore throat, coughing, and total illness symptoms, relative to nonusers. No differences were found between OC users and nonusers in NK phenotype number. These findings support the hypothesis that differences between users and nonusers in infection rates might be due to alterations in NK activity.