Context: Aromatase deficiency causes obesity and insulin resistance in aromatase knockout mice and humans with rare mutations of the aromatase gene (CYP19). Aromatase inhibitors are a commonly prescribed therapy in post-menopausal breast cancer. Objective: We hypothesized that aromatase inhibitors induce obesity and insulin resistance when used in treatment of breast cancer. Design: Case-control study Setting: University teaching hospital Participants: 20 post-menopausal breast cancer patients, treated with aromatase inhibitor and 20 age-matched controls. Main outcome measures: Primary outcome measure was insulin sensitivity index – Matsuda, derived from a 75g oral glucose tolerance test. Body composition was assessed by DEXA and subcutaneous adipose tissue biopsies obtained for assessment of mRNA transcript levels. Data are mean ± SEM (inhibitor vs controls). Results: Aromatase inhibitor therapy was associated with significantly lower insulin sensitivity (5.15 ± 0.45 vs. 6.80 ± 0.64, P = 0.041), higher peak insulin concentration following OGTT (693.4 ± 78.6 vs. 527.6 ± 85.5 pmol/L, P = 0.035), greater percentage body fat (38.4 ± 1.0 vs. 34.6 ± 1.3 %, P = 0.026), and higher plasma leptin concentration (23.5 ± 2.8 vs. 15.5 ± 2.3 ng/mL, P = 0.035). Conclusions: Women who received aromatase inhibitors for post-menopausal breast cancer have greater percentage body fat and insulin resistance compared to controls with no history of breast cancer.