Inappropriate activation or blockage of inhibition of the complement system could cause tissue damage in autoimmune diseases particularly rheumatoid arthritis (RA). CD55 and CD59 are proteins with complement regulatory (Creg) properties that ensure cell and tissue integrity when this system is activated. The aim of this study was to evaluate the expression of CD55 and CD59 complement regulatory proteins on peripheral blood cells of RA patients and its association with disease activity. Seventy RA patients clinically diagnosed and classified as RA according to the American College Of Rheumatology/European Leagues against Rheumatism (ACR/EULAR) revised criteria for the classification of RA (2010), were included in our study with mean age of 40.32±2.27 years, including 58 (82.9 %) females and 12 males (17.1 %). They were attending the Department of Rheumatology and Rehabilitation, Faculty of Medicine, Sohag University during the period from June 2012 to August 2013. The clinical parameters of disease activity were determined, including the 28-joint disease activity score (DAS28), C-reactive protein (CRP), and rheumatoid factor (RF) levels. The patients were subdivided into active disease group (n=50) with DAS28 score higher than 5.1 (Group I); and remission group (n=20) with DAS28 score less than 2.6 (Group II). Twenty healthy individuals with mean age 33.44±7.09 years, including 14 (70%) females and 6 males (30%) were randomly selected as the control group (Group III). Flowcytometric analyses of expression of CD55 and CD59 complement regulatory proteins on erythrocytes, T lymphocytes, B lymphocytes, and neutrophils of all the study population were performed. The correlations between the expression of CD55 and CD59 complement regulatory proteins on peripheral blood cells and disease activity parameters of patients with RA were determined. Results: In RA patients, CD55 and CD59 were significantly decreased on red blood cells in comparison to control group. The mean fluorescence intensity (MFI) of CD55 and CD59 on RBCs were highly significantly lower in RA patients both in active and in remission stage of the disease than those of healthy controls (p < 0.01). As MFI for CD55 on RBCs was 9.07 ± 4.05 arbitrary units for patients and 21.33 ± 5.87 for healthy group. CD59 MFI was 28.87 ± 7.40 in patient group and 47.4 ± 7.41 in healthy group. The MFI of CD55 on neutrophils was significantly lower (p < 0.05) in RA patients in active stage of the disease and was highly significantly (p < 0.01) lower in remission stage of the disease than those of healthy controls. As MFI of CD55 on neutrophils was 85.63 ±13.02 arbitrary units for patients and 93.44 ± 6.65 for healthy group. CD59 MFI was 78.79 ± 12.29 in patient group and 78.94 ± 6.16 in healthy group. The MFI of CD55 and CD59 on B Lymphocytes were significantly lower in RA patients in remission stage of the disease than those of healthy controls. As MFI of CD55 on B Lymphocytes was 3.87 ± 2.99 arbitrary units for patients and 4.94 ± 2.76 for healthy group. CD59 MFI was 2.05 ± 1.62 in patient group and 2.78 ±1.45 in healthy group. Only the MFI of CD59 on T lymphocytes was significantly lower (p < 0.05) in RA patients in active stage of the disease. As MFI of CD55 on T Lymphocytes was 20.22 ± 6.36 arbitrary units for patients and 23.27 ± 4.66 for healthy group. CD59 MFI was 21.93 ± 5.42 in patient group and 26.16 ± 4.60 in healthy group. In addition, a significant positive correlation between CD55 and CD59 expression on the patients' peripheral blood cells and the disease activity was found; as besides confirming the decreased expression of CD55 and CD59, it was demonstrated that the higher the disease activity, the lower their expression on peripheral blood cells . Conclusion: The expression of CD55 and CD59 is down-regulated on peripheral blood cells of patients with RA; which may contribute to the pathogenesis of RA and it can be an indicator of disease activity and help in patients' follow-up.