Objects Invasive pulmonary mold infection usually has devastating outcomes. Timely differentiation between invasive pulmonary aspergillosis (IPA) from pulmonary mucormycosis (PM) is critical for treatment decision-making. However, information on IPA and PM differentiation is limited. Methods We conducted a retrospective, multicenter, observational study, with proven and probable IPA and PM patients from January 2004 to December 2017. Demographics, clinical manifestations, image reports, histopathological findings and outcomes were analyzed. Results A total of 47 IPA (34 proven and 13 probable) and 22 PM (21 proven and 1 probable) cases were analyzed. The majority of tissues (80% in IPA and 67% in PM) were obtained using bronchoscopy. While influenza infection was independently correlated to IPA, prior voriconazole exposure was independently associated with PM (p=0.036, p=0.043, respectively). The positive culture rate for PM was lower than that for IPA (41% vs. 69%, p=0.0363). The galactomannan (GM) level from serum and bronchoalveolar lavage (BAL) fluid was higher in IPA than in PM (3.1 ± 0.5 vs 0.7 ± 0.6, p=0.0313; 4.3 ± 0.6 vs. 1.5 ±1.0, p=0.0375, respectively). The overall mortality rate was 64%, which was similar among IPA and PM groups. Systemic steroid exposure and high Acute Physiology and Chronic Health Evaluation II (APACHE II) scores on admission were independently correlated to mortality in IPA (p=0.024), and concurrent bacterial sepsis predicted the in-hospital mortality among PM patients (p=0.029). Conclusions Influenza infection and prior exposure to voriconazole may help physicians to differentiate IPA and PM. Bronchoscopy-guided biopsy and lavage specimen provide timely and definite diagnosis. While the prognosis of IPA is associated with systemic steroid exposure and higher APACHE II scores on admission, concurrent bacterial sepsis is the only independent predictor for mortality in PM.