A depression in feed intake and growth often occurs in the weaned pig. Spray-dried plasma is often added to nursery diets in an attempt to stimulate feed intake during this lag. The current study evaluated gene expression of appetite regulators in hypothalamus and adipose tissue 4 d after weaning. Barrows (2 wk of age) were cross-fostered to a sow (SOW, n = 8) or weaned and fed a nursery diet containing either 0 or 7% spray-dried plasma (NP, n = 8, and SDP, n = 8, respectively). Piglets were allocated such that 2 size groups existed within each experimental group: small (3.5 to 4.3 kg of BW piglets) and large (4.6 to 5.7 kg of BW piglets) subsets, based on weaning weight (WW), existed within each experimental group: small (3.5 to 4.3 kg piglets) and large (4.6 to 5.7 kg piglets). Animals were killed 4 d after weaning for tissue collection. There was a weaning group x WW interactive effect (P < 0.05) on hypothalamic neuropeptide Y messenger RNA expression, such that expression was least in the small SDP piglets. No WW or weaning group effects were seen on adipose leptin, hypothalamic leptin receptor, or hypothalamic proopiomelanocortin gene expression. An effect of WW was seen on hypothalamic neuropeptide Y, agouti-related protein, orexin, and type 2 orexin receptor gene expression, such that large pigs expressed greater amounts of these transcripts (P < 0.002). Strong positive correlations in gene expression were found among all of these genes, whose products are known to stimulate appetite. Partial correlation controlling for initial WW revealed that preweaning size explained most if not all of these associations. These data suggest that the postweaning expression of appetite-regulating genes is more dependent on preweaning conditions than on weaning diet.