To assess the role of genetic changes in sensitivity to leptin hormone in contributing to responses to long-term selection for fatness, leptin was administered to a long-term fat selected (F) and a control line (C) of mice. These lines differ almost three fold in their percentage of fat (fat%) at about 15 weeks of age. Treated (T) animals received twice-daily intraperitoneal injections of 5 mg/kg leptin from 91 to 105 days of age; untreated (U) animals received equivolume injections of phosphate-buffered saline. Treated compared with untreated animals in both lines had significantly (P<0·05) lower mean body weight, food intake and fatness at the end of test (fat%: CT 3%, CU 7·4%, FT 14·9%, FU21·1%). The differences in response between the lines [(CT−CU)−(FT−FU)] were all non-significant (P>0·05), however. There was a very wide range of fatness (estimated from dry matter content) among FT animals (3–29%), much higher than in FU (15–31%), CT (0·7–6·4%) and CU (2–15%) animals. While sensitivity to leptin remains in the fat line, response appears to vary among animals at the dose level used.