Angiopoietin-like protein 2 (Angptl2) plays a key role in chronic inflammation and tissue remodeling. We evaluated whether serum Angptl2 is associated with interstitial lung disease (ILD) in primary Sjogren's syndrome (pSS) patients. A total of 158 consecutive pSS patients and 25 normal healthy controls, which completed lung HRCT, were enrolled in our research. The levels of serum Angptl2 and TGF-beta 1 were measured by enzyme-linked immunosorbent assay. We investigated the correlation between the activity indexes of pSS-ILD patients and the serum Angptl2 levels. There were 71 of 158 (44.94%) patients interpreted pSS-ILD by radiologists at the initial presentation. The median interquartile range for serum Angptl2 was 16.55 ng/mL (range 10.82-41.07) in pSS patients, compared with 6.05 ng/mL (range 3.53-9.91) in normal healthy controls (P < 0.001). Importantly, differences between Angptl2 levels in pSS-ILD patients and pSS-N-ILD patients were also statistically significant [29.80 ng/mL (range 15.42-54.40), 14.75 ng/mL (range 9.85-40.48), P < 0.001]. A logistic regression analysis suggested that anti-Ro52, serum Angptl2 and DLCO were associated with pSS patients with interstitial lung disease, with aORs and 95% CIs of 2.06 (1.14-7.65), 4.13 (1.25-15.89) and 9.51 (2.10-37.74), respectively. Moreover, anti-Ro52 (r(s) = 0.48, P = 0.016) and TGF-beta 1 (r(s) = 0.64, P = 0.003) were significantly correlated with the serum Angptl2 in pSS-ILD patients. And, in pulmonary function tests, the serum Angptl2 was significantly correlated with DLCO (r(s) = - 0.40, P = 0.009) and FVC (r(s) = -0.37, P = 0.020). Serum Angptl2 may display a peculiar role in the pathogenesis of pSS-ILD and might be a potential biomarker.