Acute administration of PYY(3-36) results in a reduction in food intake in several different vertebrates. However, long-term continuous administration of PYY(3-36) causes only a transient reduction in food intake thus potentially limiting its therapeutic efficacy. We hypothesized that a fall in leptin levels, associated with reduced food intake could contribute to the transient anorectic effects of continuous PYY(3-36) infusion and thus that leptin replacement might prolong the anorectic effects of PYY(3-36). Seven day administration of 100 µg/kg BW/day PYY(3-36) using osmotic mini-pumps caused a significant reduction in food intake of ad lib fed rats, but only for the first 2 days post-implantation. Circulating levels of leptin were reduced 1 day following continuous infusion of PYY(3-36) and combined leptin infusion at a dose of leptin that had no anorectic effects on its own (100 µg/kg BW/day) prolonged the anorectic actions of PYY(3-36) in ad lib fed rats for up to 6 days post-implantation and yielded reduced weight gain compared to either peptide alone. The inhibitory effects of 100 µg/kg BW/day PYY(3-36) on food intake were absent in rats refed after a 24 hour fast and substantially reduced at a dose of 1000 µg/kg BW/day PYY(3-36). Leptin replacement was unable to recover the anorectic effects of PYY(3-36) in fasted rats. Our results suggest that an acute fall in leptin levels is not solely responsible for limiting duration of action of chronic PYY(3-36) infusion, yet chronic co-administration of a sub-anorectic dose of leptin can extend the anorectic effects of PYY(3-36).