Background Rheumatoid arthritis (RA)-associated diffuse interstitial lung disease (ILD) is a common extra-articular manifestation that causes significant morbidity and mortality. Anti-citrullinated peptide antibodies (ACPA) are a valuable marker in assessing worsening of articular injury in patients with RA. We studied the correlation of ACPA in patients with RA with ILD. Patients and methods A randomized controlled trial involving 45 patients with RA fulfilling the American College of Rheumatology/European League Against Rheumatism criteria was conducted. Patients were grouped into two groups: group I: RA with ILD (15 cases) and group II: RA without ILD (30 cases). Data, such as disease activity score (DAS), disease duration, ACPA by enzyme-linked immunosorbent assay technique, pulmonary functions, and radiographic evidence of ILD by chest highresolution computed tomography, with estimation of ground-glass and reticular pattern scores, were collected. Results A total of 34 (75.6%) cases were ACPA positive, whereas 11 (24.4%) cases were anti-cyclic citrullinated peptide negative. Diffusion capacity for carbon monoxide reduced significantly in RA with ILD group (P=0.002). Reticular and DAS were significantly high in the ACPA-positive group (P=0.005). Moreover, there were statistically significant increases in erythrocyte sedimentation rate, C-reactive protein, and platelets but statistically significant decrease in white blood cells in in the ACPA-positive group. ACPA positively correlated with DAS (r=0.610) and erythrocyte sedimentation rate (r=0.472). RA disease duration positively correlated with the presence of ILD (P=0.000) and showed a strong negative correlation with diffusion capacity for carbon monoxide (P=0.04). The positive predictive value of positive ACPA was 78.8 for ILD, of which, 70% for ground glass, 100% for the reticular pattern. Conclusion ACPA is positively correlated with the presence of ILD in patients with RA.