Background and Objectives The number of patients with pulmonary Mycobacterium avium complex (MAC) disease is increasing worldwide, especially among middle-aged women and never-smokers. Although sex and smoking status have attracted attention as predictors of the development and exacerbation of pulmonary MAC disease, the exact associations remain unknown.The aim of the present study was to clarify the associations of sex and smoking status with the clinical characteristics of pulmonary MAC disease and to identify the predictors of exacerbations of pulmonary MAC disease. Methods From April 2011 to May 2016, 128 MAC patients at our institute were newly diagnosed with pulmonary MAC disease according to the 2007 American Thoracic Society/Infectious Disease Society guideline. Their medical records were retrospectively examined for their clinical findings. The radiological findings at the time of the diagnosis and 1 year later were evaluated. Clinical characteristics were compared by smoking status and sex. To identify the natural predictors of exacerbation, multivariable analysis was performed with the data of 80 treatment-naïve patients. Results Female, never-smoker, and nodular/bronchiectatic (NB) type were common in patients with pulmonary MAC disease. Univariate analysis of data from treatment-naïve subjects showed that female, never-smoker, fewer lung diseases other than MAC, extensive radiological findings, and ≥3 lobes involved were significantly associated with exacerbations. On multivariate analysis, fewer lung diseases other than MAC, extensive radiological findings, and ≥3 lobes involved were significantly associated with exacerbations, but female and never-smoker were not. Conclusions In this study, the presence of extensive radiological findings, especially abnormal shadows in ≥3 lobes and absence of lung diseases other than MAC, rather than sex and smoking status, was a predictor of exacerbations of treatment-naïve pulmonary MAC disease.