Background: Little study has investigated the differences between Talatomyces marneffei (T. marneffei) respiratory infection and tuberculosis and the prognostic factors of such infection. This study investigated the characteristics and prognostic factors of T. marneffei infections with respiratory lesions and the causes of misdiagnosis. Methods: Clinical characteristics and prognoses of patients with T. marneffei infections with respiratory system lesion were investigated. T. marneffei diagnosis followed isolation from clinical specimens using standard culture, cytology, and histopathology. Survival curves were estimated by using Kaplan-Meier analysis, with log-rank test to compare differences in survival rates between groups. Univariate and multivariate Cox regression analyses were also performed to assess significant differences in clinical characteristics of overall survival. Results: Of 126 patients diagnosed with T. marneffei infections, 63 (50.0%) had T. marneffei respiratory system infections; 38.1% (24/63) were misdiagnosed as having tuberculosis. Human immunodeficiency virus (HIV) infection, CD4/CD8 < 0.5, percentage of CD4⁺ T cells <42.8%, and length of time from onset to confirmation of diagnosis >105 days were potential risk factors for poor prognoses. Length of time from onset to confirmation of diagnosis persisted as an independent predictor of all-cause mortality in multivariate analysis (odds ratio: 0.083, 95.0% confidence interval: 0.021–0.326, P < 0.001). However, the size of the lung lesions, dyspnea, thoracalgia, mediastinal lymphadenopathy, and pleural effusion did not significantly predict overall survival. There was no significant difference in prognosis according to the type of treatment. Conclusions T. marneffei infections involving the respiratory system are common. The critical determinants of prognosis are HIV infection, CD4/CD8, percentage of CD4⁺ T cells, type of treatment, and the time range from onset to confirmation of diagnosis. Rapid and accurate diagnosis is crucial for improving prognosis.