Metabolic syndrome after transplantation is a major concern following solid organ transplantation (SOT). The CREB-regulated transcription co-activator 2 (CRTC2) regulates glucose metabolism. The effect of CRTC2 polymorphisms on new-onset diabetes after transplantation (NODAT) was investigated in a discovery sample of SOT recipients (n1 = 197). Positive results were tested for replication in two samples from the Swiss Transplant Cohort Study (STCS, n2 = 1294 and n3 = 759). Obesity and other metabolic traits were also tested. Associations with metabolic traits in population-based samples (n4=46’186, n5 = 123’865, n6>100,000) were finally analyzed. In the discovery sample, CRTC2 rs8450-AA genotype was associated with NODAT, fasting blood glucose and body mass index (Pcorrected<0.05). CRTC2 rs8450-AA genotype was associated with NODAT in the second STCS replication sample (odd ratio (OR) = 2.01, P = 0.04). In the combined STCS replication samples, the effect of rs8450-AA genotype on NODAT was observed in patients having received SOT from a deceased donor and treated with tacrolimus (n = 395, OR = 2.08, P = 0.02) and in non-kidney transplant recipients (OR = 2.09, P = 0.02). Moreover, rs8450-AA genotype was associated with overweight or obesity (n = 1215, OR = 1.56, P = 0.02), new-onset hyperlipidemia (n = 1007, OR = 1.76, P = 0.007), and lower high-density lipoprotein-cholesterol (n = 1214, β = -0.08, P = 0.001). In the population-based samples, a proxy of rs8450G>A was significantly associated with several metabolic abnormalities. CRTC2 rs8450G>A appears to have an important role in the high prevalence of metabolic traits observed in patients with SOT. A weak association with metabolic traits was also observed in the population-based samples.