The influence of genetic factors in rheumatoid arthritis (RA) has been described, including several cytokine genes such as transforming growth factor β (TGF-β) with regulatory effects on lymphocytes, dendritic cells, macrophages, chondrocytes, and osteoblasts, which are important in the RA pathogenesis. The G915C TGF-β1 polymorphism has been associated with soluble TGF-β1 (sTGF-β) serum levels. Thus, we studied the association of G915C (Arg25Pro) TGF-β1 polymorphism with sTGF-β1 serum levels in RA. We enrolled 120 RA patients and 120 control subjects (CS). The G915C TGF-β1 polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, and sTGF-β1 serum levels were quantified using an ELISA kit. The genotype frequency of G915C TGF-β1 polymorphism in RA and CS was G/G (91.7%), G/C (8.3%), C/C (0%) and G/G (85.8%), G/C (14.2%), C/C (0%), respectively, without significant differences. Moreover, the G/G TGF-β1 genotype carriers presented the highest disability index evaluated for the Spanish HAQ-DI score (P < 0.001). In addition, the sTGF-β1 serum levels were higher in RA (182.2 ng/mL) than CS (160.2 ng/mL), there was not significant difference. However, we found a positive correlation between the sTGF-β1 serum levels and the functional class (r = 0.472, P = 0.023). In conclusion, the G915C (Arg25Pro) TGF-β1 polymorphism is not associated with RA, but the sTGF-β1 serum levels are related with the functional class in RA.