The level of serum 25-Hydroxyvitamin D [25(OH)D] has high heritability, suggesting that genes may contribute to variations in serum 25(OH)D level and vitamin D dose-response. As vitamin D deficiency has been linked to numerous diseases, understanding how genetic variation contributes to vitamin D dose-response is important for personalized vitamin D treatment and cost-effective disease prevention. To identify genetic variants responsible for vitamin D status and dose-response, we performed two vitamin D3 and calcium clinical supplementation trials in 2,207 postmenopausal Caucasian women. We examined the association of 291 SNPs with baseline serum 25(OH)D levels and 25(OH)D dose-response. Five SNPs, rs10500804 (P = 4.93 × 10-7), rs2060793 (P = 6.63 × 10-7), rs10741657 (P = 1.49 × 10-6), rs10766197 (P = 1.05 × 10-5) and rs11023380 (P = 7.67 × 10-5) in the CYP2R1 gene, as well as 6 SNPs, rs4588 (P = 7.86 × 10-7), rs2298850 (P = 1.94 × 10-6), rs1155563 (P = 6.39 × 10-6), rs705119 (P = 2.80 × 10-5), rs705120 (P = 1.08 × 10-4) and rs222040 (P = 1.59 × 10-4) in the GC gene were associated with baseline serum 25(OH)D levels. SNP rs11185644 near the RXRA was significantly associated with 25(OH)D dose-response (P = 1.01 × 10-4). Our data suggest that polymorphisms in the CYP2R1 and GC gene may contribute to variation in baseline serum 25(OH)D concentration, and that polymorphism rs11185644 may contribute to variation in 25(OH)D dose-response in healthy postmenopausal Caucasian women.