The purpose of this study was to observe both the changes of soluble intercellular adhesion molecule-1 (sICAM-1) and ghrelin in adolescents with family history of type 2 diabetes (FHD) and the relationship between sICAM-1 and ghrelin. This case–control study included 63 adolescents (boys/girls 29/34, age 14.1 ± 0.7 years) without FHD (FHD−) and 67 adolescents (boys/girls 33/34, age 14.0 ± 0.8 years) with FHD (FHD+). Anthropometric measurements, including height, weight, waist circumference (WC), and blood pressure, were obtained. Blood samples were collected, and fasting plasma glucose (FPG), serum lipids, true insulin, sICAM-1, and ghrelin were assayed. The results showed that the age and gender were similar in two groups (P > 0.05). Body mass index (BMI), WC, FPG, fasting insulin, HOMA-IR, and sICAM-1 were all significantly higher in the FHD+ group than in the FHD− group (P P r = 0.178, P = 0.043), fasting insulin (r = 0.195, P = 0.026), HOMA-IR (r = 0.197, P = 0.024), and ghrelin (r = 0.290,P = 0.001). After multivariate analysis, the ghrelin (β = 0.788, 95 % CI: 0.416–1.159, P = 0.000) and HOMA-IR (β = 0.106, 95 % CI: 0.045–0.167, P = 0.001) maintained an independent association with sICAM-1. These findings led to the conclusion that endothelial dysfunction and decline of ghrelin were found in adolescents with family history of diabetes. The decline of ghrelin maybe a protection mechanism for endothelial function in adolescents with family history of diabetes and should be examined in future studies.