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This study aimed to characterize for the first time in vitro5‐HT4receptors in the canine gastrointestinal tract. For this purpose, we used circular muscle strips of the canine isolated rectum.In the presence of methysergide (60 μM), 5‐HT induced relaxation of methacholine (1 μM)‐precontracted muscle strips, yielding a monophasic sigmoidal concentration‐relaxation curve (pEC507.2±0.07).Tetrodotoxin (0.3 μM) did not affect the curve to 5‐HT, suggesting the inhibitory 5‐HT receptor is located on the smooth muscle. Granisetron (0.3 μM) did also not affect the curve to 5‐HT, which excludes the 5‐HT3receptor mediating the relaxation to 5‐HT. The presence of methysergide rules out the involvement of 5‐HT1, 5‐HT2or 5‐HT7receptors.5‐HT, the selective 5‐HT4receptor agonists R076186, prucalopride (R093877) and SDZ HTF‐919 and the 5‐HT4receptor agonists cisapride and 5‐MeOT relaxed the muscle strips with a rank order of potency R076186=5‐HT>cisapride>prucaloprideSDZ HTF‐919>5‐MeOT.The selective 5‐HT4receptor antagonists GR 125487, RS 39604 and GR 113808 competitively antagonized the relaxations to 5‐HT, yielding pKBestimates of 9.7, 7.9 and 9.1, respectively. The selective 5‐HT4receptor antagonist SB 204070 shifted the curve to 5‐HT rightward and depressed the maximal response (apparent pA210.6). GR 113808 (10 nM) produced a parallel rightward shift of the curve to the selective 5‐HT4receptor agonists R076186 (pA28.8).It is concluded that 5‐HT induces relaxation of the canine rectum circular muscle through stimulation of a single population of smooth muscle 5‐HT4receptors. For the first time, a non‐human species was shown to exhibit relaxant 5‐HT4receptors in the large intestine.