Abstract This was a comparative study of side effects and acceptability of low-dose pills administered by the oral and vaginal rout. In an experimental clinical trial study, undesirable side effects of nausea, dysmenorrhea, breast tenderness, gastrointestinal disorders, vertigo, headache, and breakthrough bleeding (BTB) were studied. The participants of the case and the control groups were the same women. The side effects were compared in 143 women using contraceptive pill containing 150 μg levonorgestrel and 30 μg ethinyl estradiol by vaginal and oral route. The efficacy and acceptability were evaluated. The side effects among the patients who used the contraceptive pills orally were significantly higher than among those who used the vaginal route (p < 0.0001). BTB occurred more often with the oral route, but there was no significant difference between their incidences (p = 0.267). Most participants in this study expressed a high level of acceptability with the vaginal route. There was only one unwanted pregnancy, which occurred when the participant used the contraceptive pill vaginally, but used it incorrectly. Using the contraceptive pill administered by vaginal route is a safe method with fewer side effects and more acceptability when compared with the oral route.