Background Progestin-only contraceptive pills (POP) are commonly reserved for women with medical comorbidities but in actuality, POPs can be safely used by anyone wanting to prevent pregnancy. This wide safety profile makes them an ideal candidate for being available over the counter without a prescription, but adherence issues may be more common with over-the-counter use. We need a better understanding of the ability of POPs to prevent pregnancy when adherence issues occur in the form of a missed or delayed pill. Objective This study aims to determine cervical mucus characteristics following a 6-hour delayed pill intake or after one missed pill as compared to typical daily use of norgestrel 75 mcg. Methods This prospective, multicenter, randomized, crossover study assesses the effect of norgestrel 75 mcg (Opill) on cervical mucus and ovarian activity during reported compliant daily use, after a 6-hour delayed intake mid cycle, and after a mid-cycle missed pill. Subject participation will last approximately 4.5 months. We will recruit at 2 US sites: Oregon Health & Science University, Portland, Oregon and University of California Davis Health, Sacramento, California. Reproductive-aged subjects with regular menstrual cycles (21-35 days), BMI <32 kg/m2, and proven ovulation (screening luteal phase progesterone >3 ng/mL [>10 nmol/L]) are eligible to enroll. Participants cannot be at risk for pregnancy during the study period and not use other hormonal methods. Norgestrel 75 mcg will be taken at the same time daily except for one day in each of treatment periods 2 and 3, when the pill will be taken either 6 hours late (delayed pill) or omitted completely (missed pill). Every 3-4 days, we will monitor subjects for follicular activity with transvaginal ultrasound (TVUS) examination, cervical mucus, and blood sampling for ovarian hormones and gonadotropins. Subjects will undergo serial cervical mucus sampling on the days with missed and delayed pill intake at 8 hours after pill intake on the day before the delayed or missed pill, 3 hours following the scheduled time of pill intake if intake was delayed, 6 hours after the scheduled time if intake was omitted, and on the next day 30 minutes before the time of scheduled pill intake. The primary objective of the study is to determine the effect of a delayed or omitted pill intake on cervical mucus characteristics based on a modified Insler score compared to reported daily use. Results Our protocol was successfully approved by a central institutional review board (Advarra, Columbia, MD), received ethical approval on March 23, 2018, and was registered with ClinicalTrials.gov (NCT03585712). As of January 2020, the study completed enrollment of 52 subjects. Analyses are pending. Conclusions Our protocol was approved by a central review board, and study procedures were successfully executed with completed proposed enrollment. Trial Registration ClinicalTrials.gov NCT03585712; https://clinicaltrials.gov/ct2/show/NCT03585712 International Registered Report Identifier (IRRID) DERR1-10.2196/29208