Background: HLA-DRB1 gene variation, especially DRB1*04 and  DRB1* 10, was found to be associated with RA risk, and it may be involved in the alteration of biochemical and hematological indicators. RA patients with HLA-DRB1*04 or *10 gene variants were evaluated for the aforesaid indicators. Methods: The biochemical and hematological indicators of 100 healthy controls and 120 RA patients with HLA-DRB1*04 or HLA-DRB1*10 gene variants were examined. The genotyping variants of all HLA genes were determined using PCR (specific primer). CBC, CRP, and ESR were measured using an automated analyzer and ACPA by ELISA. Results: RA patients have greater rates of DRB1*04 and *10 gene variants than healthy controls (9.6% vs. 5.1%, P = 0.038 and 14.2% vs. 8.2%, P = 0.042). Compared with the healthy controls, PLT, LY, NE, MO, NLR, PLR, CRP, and ESR were remarkably higher in RA patients or those with DRB1*04 or *10 gene variants (P = 0.031, < 0.001, 0.045, 0.002, 0.018, 0.011, < 0.001, and < 0.001). In contrast, RBC, Hb, MPV, and BA levels dropped (P = 0.010, 0.048, 0.021, and 0.039) in the patients. RA patients with the HLA-DRB1*04 or *10 gene variants have considerably higher levels of LY, NE, NLR, PLR, CRP, and ESR than healthy controls (P = < 0.001, < 0.001, 0.036, 0.004, < 0.001, and < 0.001). In contrast, RBC, Hb, and BA decreased significantly (P < 0.001). Conclusion: The HLA-DRB1*04 or *10 gene variants were associated with RA risk and contributed to the population's biochemical and hematological alterations.