ABSTRACT: Dysbiotic airway microbiota play important roles in the inflammatory progression of asthma, and exploration of airway microbial interactions further elucidates asthma pathogenesis. However, little is known regarding the airway bacterial-fungal interactions in asthma patients. We conducted a cross-sectional survey of the sputum bacterial and fungal microbiota from 116 clinically stable asthma patients and 29 healthy controls using 16S rRNA gene and ITS1 sequencing. Compared with healthy individuals, asthma patients exhibited a significantly altered microbiota and increased bacterial and fungal alpha diversities in the airway. Microbial genera Moraxella, Capnocytophaga, and Ralstonia (bacteria) and Schizophyllum, Candida, and Phialemoniopsis (fungi) were more abundant in the asthma airways, while Rothia, Veillonella and Leptotrichia (bacteria) and Meyerozyma (fungus) were increased in healthy controls. The Moraxellaceae family and their genus Moraxella were significantly enriched in asthma patients compared with healthy controls (80.5-fold, P = 0.007 and 314.7-fold, P = 0.027, respectively). Moreover, Moraxellaceae, along with Schizophyllum, Candida, and Aspergillus (fungal genera), were positively associated with fungal alpha diversity. Correlation networks revealed 3 fungal genera (Schizophyllum, Candida, and Aspergillus) as important airway microbes in asthma that showed positive correlations with each other and multiple co-exclusions with other common microbiota. Moraxellaceae members were positively associated with asthma-enriched fungal taxa but negatively related to several healthy-enriched bacterial taxa. Collectively, our findings revealed an altered microbiota and complex microbial interactions in the airways of asthma patients. The Moraxellaceae family and their genus Moraxella, along with 3 important fungal taxa, showed significant interactions with the airway microbiota, providing potential insights into the novel pathogenic mechanisms of asthma.