Objective To investigate the clinical characteristics of interstitial pneumonia patients with positive anti-signal recognition particle antibody (SRP-IP), and compare those with interstitial pneumonia patients with positive anti-Jo-1 antibody (Jo1-IP). Methods Clinical data of SRP-IP patients admitted to Department of Respiratory and Critical Care Medicine of Drum Tower Hospital affiliated to Nanjing University Medical School from May 2017 to May 2021, including clinical manifestations, laboratory examinations, pulmonary function tests and radiographic types, were retrospectively analyzed. The results were compared with those of Jo1-IP patients admitted during the same period. Results The SRP-IP patients were older than Jo1-IP patients (P=0.044). There were no significant differences in clinical manifestations or pulmonary function tests results between the two groups. The proportion of SRP-IP patients combined with positive anti-EJ antibody (P<0.001) or perinuclear anti-neutrophil cytoplasmic antibody (P=0.028) was significantly higher than that of Jo1-IP patients, while the proportion of SRP-IP patients combined positive anti-Ro-52 antibody was significantly lower than that of Jo1-IP patients (P=0.009). The erythrocyte sedimentation rate (ESR) of SRP-IP patients was faster than that of Jo1-IP patients (P=0.026). The serum IgM level (P=0.039) and peripheral NK cell counts (P=0.013) of SRP-IP patients were significantly lower than those of Jo1-IP patients. The most common chest CT findings in SRP-IP patients were organizing pneumonia and the proportion of usual interstitial pneumonia in SRP-IP patients was higher than that of Jo1-IP patients (P=0.032). The levels of creatine kinase (P=0.010), creatine kinase myocardial brand (P=0.025) and alanine aminotransferase (P=0.045) in interstitial pneumonia patients with high titer (++~+++) SRP antibody were higher than those in interstitial pneumonia patients with low titer (+) SRP antibody. SRP-IP and Jo1-IP patients were mainly treated with glucocorticoids combined with or without immunosuppressants, and there was no significant difference in the choice of treatment between the two groups. The proportion of patients with Jo1-IP evaluated as improved was significantly higher than that of patients with SRP-IP (p=0.005), while the proportion of patients with SRP-IP evaluated as stable was significantly higher than that of patients with Jo1-IP (P=0.035). The mortality of SRP-IP patients within 3 months was significantly higher than that of Jo1-IP patients (P=0.028). Conclusion Compared with Jo1-IP patients, SRP-IP patients are older, have faster ESR, are more likely to be combined with other autoantibodies, have lower serum IgM level and peripheral blood NK cell count, have more UIP imaging manifestations, and have a worse short-term prognosis.