ObjectivesTo compare clinical outcomes in patients with severe pneumonia according to the diagnostic strategy used.MethodsIn this retrospective, nested, case–control study, patients with severe pneumonia who had undergone endotracheal aspirate (ETA) metagenomic next-generation sequencing of (mNGS) testing (n= 53) were matched at a ratio of 1 to 2 (n= 106) by sex, age, underlying diseases, immune status, disease severity scores, and type of pneumonia with patients who had undergone bronchoalveolar lavage fluid (BALF) mNGS. The microbiological characteristics and patient’s prognosis of the two groups were compared.ResultsAn overall comparison between the two groups showed no significant differences in bacterial, fungal, viral, or mixed infections. However, subgroup analysis of 18 patients who received paired ETA and BALF mNGS showed a complete agreement rate for the two specimens of 33.3%. There were more cases for whom targeted treatment was initiated (36.79% vs. 22.64%;P= 0.043) and fewer cases who received no clinical benefit after mNGS (5.66% vs. 15.09%;P= 0.048) in the BALF group. The pneumonia improvement rate in the BALF group was significantly higher than in the ETA group (73.58% vs. 87.74%,P= 0.024). However, there were no significant differences in ICU mortality or 28-day mortality.ConclusionsWe do not recommend using ETA mNGS as the first-choice method for analyzing airway pathogenic specimens from severe pneumonia patients.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12879-023-08376-9.