Peptide YY(3-36) [PYY(3-36)] is a gut-brain peptide that decreases food intake when administered by intravenous infusion to lean and obese humans, and rats. Yet, chronic administration of PYY(3-36) by osmotic minipump to lean and obese rodents produces only a transient reduction in daily food intake and weight gain. We recently showed that 1-hour intravenous infusions of PYY(3-36) every other hour for 10 days produced a sustained reduction in daily food intake, body weight and adiposity in lean rats. Here we determined whether intermittent delivery of PYY(3-36) can produce a similar response in diet-induced obese rats. During a 21-day period, obese rats (body fat>25%) received twice daily intraperitoneal infusion of vehicle (n=18) or PYY(3-36) (n=24) during hours 1-3 and 7-9 of the dark period. Rats had free access to both a 45%-fat solid diet and a 29%-fat liquid diet; intakes were determined from computer recording of changes in food container weights. In order to sustain a 15-25% reduction in daily caloric intake, the initial PYY(3-36) dose of 30 pmol/kg/min was reduced to 10 pmol/kg/min on day 10, and then increased to 17 pmol/kg/min on day 13. This dosing strategy produced a sustained reduction in daily caloric intake of 11-32%, and prevented body weight gain (8 ± 6 g vs. 51 ± 11g) and fat deposition (4.4 ± 7.6 g vs. 41.0 ± 12.8 g). These results indicate that intermittent intraperitoneal infusion of PYY(3-36) can produce a sustained reduction in food intake and adiposity in diet-induced obese rodents consuming palatable high-fat foods.