In a recent article published in CancerShui et al. observed no statistically significant relationship between circulating 25-hydroxyvitamin D (25(OH)D) and fatal prostate cancer (PCa) 1. However, an association between CYP2R1 SNPs and fatal PCa is found 1. CYP2R1 is the hydroxylase involved in the conversion of vitamin D into 25(OH)D. In the classical vitamin D endocrine system,activation of vitamin D into 1,25(OH)2D requires two successive hydroxylation steps. The first one is catalyzed by CYP2R1 in the liver and the second one by CYP27B1 in the kidneys. Then, 1,25D is released in the blood circulation and behaves as an endocrine hormone. The conversion of 25(OH)Dinto the active hormone 1,25(OH)2D by CYP27B1 is under stringent control. However, the first hydroxylation step catalyzed in the liver by CYP2R1 is constitutive and is not believed to be subjected to tight regulation. This has two important consequences: i) the regulation of liver CYP2R1 has retained little attention, and ii) circulating non-hydroxylated vitamin D is rapidly metabolized by liver CYP2R1. Therefore, 25(OH)D concentrations are considered to reflect vitamin D inputsand are used to determine the vitamin D status. A major breakthrough in our understanding on the nonskeletal effects of vitamin D is the recent discovery of autocrine/paracrine vitamin D systemsin many tissues 2 .This autocrine/paracrine signalingensures the local bioactivation of 25(OH)D into 1,25(OH)2D by extra-renal CYP27B1. In autocrine/paracrine vitamin D systems, the vitamin D metabolites are produced, act and are degraded locally without affecting serum 25(OH)D levels. Shui and coll rightly pointed out that local synthesis of 1,25(OH)2D from 25(OH)D can occur,because CYP27B1 is expressed in the prostate. However, the authors do not mention that CYP2R1 is also expressed in prostate tissue 3