The aim of this study is to evaluate the presence of antibodies to carbonic anhydrase I and/or II (ACAI and ACAII) in patients affected by connective tissue diseases (CTD) and to investigate their association with lung involvement evaluated by High resolution CT scan (HRCT). Ninety-six patients affected by CTD were studied, i.e. 33 rheumatoid arthritis (RA), 8 psoriatic arthritis (PA), 8 ankylosing spondilitis (AS), 23 Systemic Lupus Erythematosus (SLE), 10 Sjogren Syndrome (SS), and 14 Systemic Sclerosis (SSc). ACA were detected by ELISA. The lung involvement was evaluated by means of a previously described HRCT score. According to a receiver operator characteristic curve, patients were divided into those with HRCT score ≥ 10 and those with HRCT score < 10, where HRCT score ≥ 10 was predictive of interstitial lung disease. ACAI and/or ACAII were detected in 30/96 patients (31.2%) (P<0.0001 in comparison with controls). In particular, the prevalence of ACAI and/or ACAII was significantly higher in patients with RA (P = 0.002), PA (P < 0.0001), SLE (P = 0.0003) and SSc (P<0.0001). A positive correlation was found between HRCT scores and CRP or ACAI levels (P=<0.0001 and P=0.004, respectively). Thirty-nine of 96 patients (40.6%) showed a HRCT score ≥ 10 and both their CRP and ACAI levels were significantly higher when compared with patients showing a HRCT score < 10 (P<0.0006 and P = 0.0009, respectively). Moreover, C3 and C4 complement fractions inversely correlated with HRCT scores (P = 0.0004 and P<0.0001, respectively) and lower values of C3 and C4 complement fractions were found in patients with HRCT score ≥ 10 than in those with HRCT score < 10 (P = 0.014 and P = 0.007, respectively). Due to the lower levels of complement fractions detected in patients with HRCT score ≥ 10, a possible immune-complex-mediated pathogenic mechanism of lung involvement could be suggested.