Agents that can reduce the incidence of hormone receptor negative breast cancer are currently lacking. Rexinoids such as bexarotene significantly reduced mammary tumor development in preclinical mouse models. Oral bexarotene in BRCA mutation carriers significantly decreased cyclin D1 in breast cells, suggesting biological activity on breast tissue. This study evaluated topical bexarotene 1% gel applied to one unaffected breast in women at high risk for breast cancer for 4 weeks to assess safety and toxicity. Secondary objectives included assessment of bexarotene concentrations in the plasma and breast tissue. In the dose escalation phase, women were assigned to one of three different dose levels: 10 mg (1 mL) every other day, 10 mg (1 mL) daily, 20 mg (2 mL) daily. Dose-limiting toxicity (DLT) was defined as a grade 2 skin adverse event for at least 6 days or any grade 3 or 4 adverse event related to study drug. A total of 14 women were enrolled with 10 participants at the every other day dose level and 4 participants at daily dosing. Two skin DLTs were experienced at daily dosing and therefore further enrollment was discontinued per protocol. An additional 10 participants were enrolled at the MTD as part of the dose expansion phase. These individuals tolerated the treatment with minimal adverse events. Maculopapular rash at the treatment site was the most common adverse event related to study drug and resolved within a few days of discontinuation. Bexarotene was detectable in breast tissue at the 10 mg daily every other day dose.