The effect of drospirenone on plasma potassium when coadministered with nonsteroidal anti-inflammatory drugs, such as indomethacin, is unknown. An open-label crossover study investigated the effects of estradiol/drospirenone and indomethacin coadministration on plasma potassium levels in 32 postmenopausal women. Each participant received 2 treatments in random order: indomethacin alone for 5 days and estradiol/drospirenone alone for 12 days, then estradiol/drospirenone plus indomethacin for 5 days. Plasma potassium profiles (24 hours) were measured on the first and last days of indomethacin administration. No difference was seen between treatments in the area under the curve or maximum concentration of plasma potassium. No participant experienced hyperkalemia (potassium >5.5 mmol/L). Twenty-seven participants had at least 1 potassium value above the upper limit of normal (4.4 mmol/L), but these occurred during both treatments. Coadministration of estradiol/drospirenone and a nonsteroidal anti-inflammatory drug such as indomethacin is not expected to result in increased plasma potassium or hyperkalemia in healthy postmenopausal women.