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Purpose Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium. Methods Chemo-naive patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. Results Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 μg to 5000 μg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors. Conclusion Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 μg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.