Ten women were treated daily with a standard dose contraceptive tablet containing 0.25 mg levonorgestrel (LNG) in combination with 0.05 mg ethinylestradiol. Five women used the tablet vaginally, while the other five used it orally. Blood samples were taken at frequent intervals on the first day of treatment and after 1 and 2 hours on treatment days 7 and 14. Serum LNG levels were measured by radioimmunoassay, and sex hormone-binding globulin (SHBG) was quantitated by charcoal assay. On day 1, peak concentrations of LNG (5.1 ng/ml) occurred within 2 hours in the oral group, whereas in the vaginal group a peak of 2.2 ng/ml was reached after 4 hours. After 24 hours, mean serum concentrations of LNG were 1.1 and 0.69 ng/ml in the oral and vaginal groups, respectively. In both groups, mean LNG concentrations increased dramatically on days 7 and 14 compared to day 1. There was no significant difference between the two groups in LNG concentrations, except after 2 hours on day 1. SHBG levels were increased after one day of treatment. By day 14 of treatment, there was a 3.5- to 4.5-fold rise in SHBG levels from pretreatment values in both groups. However, there was no significant difference in SHBG levels between the two groups throughout the study. A high correlation was found between serum levels of SHBG and LNG in both the vaginal and oral groups. The results suggest that the increase in serum LNG levels in women receiving combined contraceptive tablets either vaginally or orally is due to increased levels of SHBG. Also, the measured concentrations of LNG in the vaginal group are consistent with the previously reported clinical contraceptive efficacy of combined contraceptive tablets administered vaginally.