In this systematic review, we assessed the safety and possible safety events of native glucose-dependent insulinotropic polypeptide (GIP)(1−42) in human studies with administration of synthetic human GIP. We searched the PubMed database for all trials investigating synthetic human GIP(1−42) administration. A total of 67 studies were included. Study duration ranged from 30 min to 6 days. In addition to healthy individuals, the studies included individuals with impaired glucose tolerance, type 2 diabetes, type 1 diabetes, chronic pancreatitis and secondary diabetes, latent autoimmune diabetes in adults, diabetes caused by a mutation in the hepatocyte nuclear factor 1-alpha gene, end-stage renal disease, chronic renal insufficiency, critical illness, hypoparathyroidism, or cystic fibrosis-related diabetes. Of the included studies, 78 % did not mention safety events, 10 % of the studies reported that no safety events were observed in relation to GIP administration, and 15 % of the studies reported safety events in relation to GIP administration with most frequently reported event being a moderate and transient increased heart rate. Gastrointestinal safety events, and changes in blood pressure were also reported. Plasma concentration of active GIP(1−42) increased linearly with dose independent of participant phenotype. There was no significant correlation between achieved maximal concentration of GIP(1−42) and reported safety events. Clearance rates of GIP(1−42) were similar between participant groups. In conclusion, the available data indicate that GIP(1−42) in short-term (up to 6 days) infusion studies is generally well-tolerated. The long-term safety of continuous GIP(1−42) administration is unknown.