The respective distribution of neuropeptide Y Y1, Y2, Y4, and Y5 receptor subtypes was investigated in rodents (rat and mouse), guinea pig, and primates (marmoset and vervet monkeys and human) brains, representing three orders of mammals. [125I] [Leu31,Pro34]PYY (total Y1-like; Y1, Y4, and Y5) and [125I]PYY3-36 (total Y2-like; Y2 and possibly Y5) binding sites were discretely but similarly distributed in the rat and mouse brain, each having its unique pattern. In contrast, surprisingly low levels of [125I]PYY3-36 binding sites were found in the guinea pig brain including in the hippocampal formation. [125I][Leu31,Pro34]PYY/BIBP3226-insensitive binding sites (Y5-like) were found in different areas of the rat and guinea pig brains. The primate brains also revealed a different distribution binding profile for these various NPY receptor subtypes. Although the human and vervet brains contained very low amounts of [125I][Leu31,Pro34]PYY sites (Y1-like) in most brain regions, except for the dentate gyrus of the hippocampus, the marmoset brain contains significant amounts of both [125I][Leu31,Pro34]PYY (Y1-like) and [125I]PYY3-36 (Y2-like) binding sites. Additionally, [125I][Leu31,Pro34]PYY/BIBP3226-insensitive binding sites were not clearly detected in the vervet and human brains. On the other hand, Y5-like binding sites were observed in few regions of the marmoset brain. Finally, [125I]hPP (Y4/Y5-like) were very discretely distributed in the rat brain, being concentrated in the paraventricular nucleus of the hypothalamus and the interpeduncular nucleus. The marmoset brain is apparently not enriched with specific [125I]hPP sites. Taken together, these data show that significant species differences exist in the level of expression and distribution of various NPY receptor subtypes in the mammalian brain.