Serum levels of 25-OH-D3 inversely correlate with the incidence of various types of cancers in the general population. Since risk factors and incidence of cancer in renal transplant recipients (RTRs) are different from the general population, this study was designed to determine whether pre-transplant 25-OH-D3 levels could be predictive of cancer risk in RTRs. Pre-transplant 25-OH-D3 levels were reviewed in 363 consecutive RTRs. The impact of 25-OH-D3 levels on development of cancer was then analyzed with respect to other known risk factors. One hundred twenty four patients (34.2%) showed vitamin D deficiency, 185 (51%) vitamin D insufficiency, and 54 (14.8%) with normal vitamin D levels. Thirty two cancers (8.8%) occurred in 32 patients. A higher incidence of cancer was observed in patients with vitamin D deficiency (13.7 % vs. 7 % for patients with vitamin D insufficiency [p=0.068] and 3.7 % for those with normal vitamin D levels [p=0.007]). 25-OH-D3 levels were lower in patients who developed cancer after transplantation (13.7 +/- 6 vs. 18.3 +/- 17.8 ng/ml; p=0.022). Age (HR, 1.06; 95% CI, 1.02 to 1.11, for each one year increase; p=0.009) and low 25-OH-D3 levels (HR, 1.12; 95% CI, 1.04 to 1.23, for every 1 ng/ml decrease; p=0.021) were independent risk factors for development of cancer. In conclusion, pre-transplant level of 25-OH-D3 is an important determinant for subsequent development of cancer after transplantation. Future studies should examine whether 25-OH-D3 supplementation can effectively decrease the incidence of cancer in RTRs.