Objective To investigate the effect of erythromycin on the contractive activity of the isolated gastric antrum smooth muscle and somatostatin (SS), vasoactive intestinal peptide (VIP), motilin (MTL), and substance P (SP) in plasma and isolated gastric antrum tissue of diabetes mellitus (DM) rat models. Methods Thirty male Sprague-Dawley rats were divided into three groups: control group (n = 10), DM group (n =10), and erythromycin group (DM models with erythromycin treatment, n = 10). A single dose of streptozotocin (100 mg/kg,dissolved in 0.1 mol/L citric acid buffer, pH4.5) was injected intraperitoneally. After 48 to 72 hours, rats with blood glucose above 16.7 mmol/L and urine glucose level to be (+++) to (++++) over one week were considered successful DM models. The resting tension, mean contractile amplitude and frequency of spontaneous change in isolated longitudinal and circular gastric antrum smooth muscle strips were measured. SS, VIP, MTL, and SP levels in plasma and gastric antrum tissue were measured using radioimmunoassay. Results (1) In the isolated gastric antrum smooth muscle strips, the gastric motility parameters were lower in DM group than those in control group except circular smooth muscle contractile amplitude and longitudinal smooth muscle contractile frequency. The gastric motility parameters were significantly strengthened in erythromycin group, compared with DM group except longitudinal smooth muscle resting tension (P ＜ 0.01). (2) Plasma SS, VIP, and MTL concentrations in DM group were higher than those in control (P ＜ 0.05), while the SP level decreased (P ＜ 0.05). In the gastric antrum, SS of DM group was significantly higher than that of control group (P ＜ 0.01), while SP and MTL levels were lower than those of control group (P ＜ 0.05 and P ＜ 0.01, respectively). However, the level of VIP in gastric antrum tissue did not change among three groups. The plasma level of SS in erythromycin group was higher than that of DM group(P＜ 0.05). (3) The blood glucose was lower in erythromycin group than DM group (P ＜ 0.01).Conclusions Erythromycin has direct effects on contractive activity of gastric smooth muscle in diabetic rats, but there are few effects on neuroendocrine peptides. Gastric-motility disorders in diabetic rats have a correlation with the changes of neuroendocrine peptide levels in plasma and gastric antrum tissue.