Background <p>Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease related to multiple environmental, genetic, and epigenetic factors. It affects the articular joints, causing damage to both cartilage and bone. Hox transcript antisense intergenic RNA (HOTAIR) exists on chromosome 12 and regulates chromatin state and epigenetic factors. Nuclear paraspeckle assembly transcript 1 (NEAT1) is located on chromosome 11 and regulates various cellular functions, including inflammation and autoimmunity. This study aimed to investigate the possible role of the long non-coding RNAs (HOTAIR and NEAT1) in RA and their correlations with RA severity.</p> Subjects and methods <p>This study included 66 participants divided into 2 groups. Group I comprised 33 RA cases and Group II comprised 33 healthy controls of matched age and sex. Laboratory investigations included a complete blood count (CBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Diagnosis of RA was confirmed by the measurement of the rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP). The DAS-28 score was used to evaluate the disease activity. Total RNA was extracted from peripheral blood mononuclear cells (PBMNCs) to assess the expression of HOTAIR and NEAT1.</p> Results <p>Both HOTAIR and NEAT1 were significantly upregulated in RA cases compared to the controls (<i>P</i> &lt; 0.001, for each). There were statistically significant positive correlations between HOTAIR and disease duration, DAS-28 score, MHAQ score, RF, and anti-CCP. Additionally, there were statistically significant positive correlations between NEAT1 and disease duration, DAS-28 score, MHAQ score, ESR, CRP, RF, and anti-CCP.</p> Conclusion <p>Upregulated LncRNAs (HOTAIR and NEAT1) may be involved in RA occurrence and may serve as potential biomarkers to assess RA severity.</p>