BACKGROUND AND OBJECTIVE: Cyclophosphamide is a teratogenic medication used in the treatment of adolescents with autoimmune disorders. This adolescent population is sexually active, does not receive adequate contraceptive care, and is at risk for unintended pregnancy. We undertook a quality improvement initiative to improve rates of pregnancy screening before intravenous cyclophosphamide administration in our adolescent girl patients. METHODS: Data were collected from the electronic medical record. The primary outcome was completion of a urine pregnancy test before intravenous cyclophosphamide infusion in girls aged 12 to 21 years between July 2011 and June 2015. Data were reviewed quarterly and an iterative quality improvement approach was used. Interventions included staff education, electronic order set updates, and a Maintenance of Certification project. Interrupted time series analysis and multivariable mixed effects logistic regression were used to evaluate trends over time and to adjust for potential confounders. RESULTS: Thirty girls received 153 cyclophosphamide infusions during the study. Pregnancy testing before medication administration increased from 25% to 100% by study completion. Infusions in the last time period were significantly more likely to be accompanied by a pregnancy test versus those in the first time period (odds ratio: 17.7; 95% confidence interval [CI]: 3.1–101.6) after adjustment for patient age, managing service, infusion setting, and insurance type. CONCLUSIONS: Our institution achieved a significant increase in standard pregnancy screening in adolescent girls receiving intravenous cyclophosphamide. The interventions most valuable in increasing screening rates were updating electronic order sets, educating staff, and physician engagement in the Maintenance of Certification program.