Objective: We aimed to study the applicability of heat shock protein 70 (HSP70) and YKL-40 serum levels as diagnostic and prognostic factors in patients with RA. Subjects and Methods: Sixty RA patients with 60 matched healthy persons were included in this study. Disease activity levels of RA were assessed by diseases activity score-28 (DAS28). Complete Blood Count (CBC), Erythrocytes Sedimentation Rate (ESR), serum C-reactive Protein (CRP), Rheumatoid Factor (RF), Anticyclic Cetrolinated Peptide (Anti- CCP), HSP70 and YKL-40 were measured. Results: HSP70 level were significantly higher in patients with severe activity (0.922 ± 0.103 ng/mL) compared to other groups (p<0.001). Interestingly, HSP70 levels in patients within remission phase were still higher than control subjects (0.372 ± 0.176 vs. 0.173 ± 0.11 ng/mL, p<0.05). Also, there was a significant difference in HSP70 level between patients in remission and patients with mild (0.478 ± 0.255 ng/mL) or moderate (0.619 ± 0.207 ng/mL) disease activity. YKL-40 also has a similar pattern of HSP70 in different grades of RA activity. It was significantly higher in patients with severe activity of RA (386.85 ± 22.61 ng/mL) compared to other groups (p<0.001) and its level in patients within remission phase was still higher than control subjects (179.0 ± 73.19 vs. 50.26 ± 11.18 ng/mL, p<0.05), with a significant difference in YKL-40 level between patients in remission and patients with mild (230.0 ± 116.15 ng/mL) or moderate (256.74 ± 89.92 ng/mL) disease activityHSP70 predicted RA at a cutoff ≥ 0.50 ng/mL with 76.09% sensitivity and 87.84 % specificity while YKL-40 predicted those having RA in levels more than 100 ng/mL with 100% sensitivity and 78.38% specificity. Conclusion: Both HSP70 and YKL-40 can be used as markers for diagnosis and monitoring of disease activity in patients with RA.