Presence of interstitial lung disease (ILD) is believed to be associated with mortality in microscopic polyangiitis (MPA); however, evidence on MPA-ILD remains lacking. Acute exacerbation (AE) refers to rapidly progressive, fatal respiratory deterioration that may develop in patients with various ILDs. No study has investigated the clinical significance of AE in MPA-ILD.We aimed to determine the clinical picture and prognostic factors, the incidence of AE and its risk factors in patients with MPA-ILD.Eighty-four consecutive patients with MPA-ILD and 95 patients with MPA-non-ILD were analyzed. We also compared 80 patients with MPA-ILD and 80 patients with idiopathic interstitial pneumonia without myeloperoxidase-anti-neutrophil cytoplasmic antibody-positivity (ILD-alone), who were matched for age, sex, and chest high-resolution computed tomography pattern.The MPA-ILD group had a higher frequency of men and smokers and was associated with higher mortality than the MPA-non-ILD group. The matched MPA-ILD group had a higher mortality rate than the matched ILD-alone group. There was no significant difference in AE incidence between the matched MPA-ILD and ILD-alone groups (1-year AE cumulative incidence rate: 7.5% and 5.2%, respectively, P = 0.75). In the MPA-ILD group, a lower percent-predicted forced vital capacity (%FVC) was independently associated with a higher mortality rate (hazard ratio [HR]: 0.96 per 1% increase, P < 0.01) and a higher AE incidence rate (HR: 0.96 per 1% increase, P = 0.01). On multivariable Cox regression analysis with time-dependent covariates, developing AE during their clinical course was strongly associated with shorter survival (HR: 17.1, P < 0.001).MPA-ILD represented a distinct phenotype with poor prognosis. Lower %FVC was an independent prognostic factor. Patients with lower %FVC had a risk of developing AE, which was a strong prognostic determinant. The specific management for MPA-ILD and AE should be established.