Therefore, this study aimed to investigate the associations and gene–gene interactions of four SNVs in vitamin D metabolism genes, rs10741657 (CYP2R1), rs10877012 (CYP27B1), rs4809959 (CYP24A1), and rs731236 TaqI (VDR) with hypovitaminosis D, RA, and its clinical disease activity in a Mexican mestizo population. This evidence concerns the gene CYP2R1 and rheumatoid arthritis.