Background: Genes make microorganisms resistant to antibiotics are overwhelmingly present in environments, and those in the air seem to consistently worsen human health, especially in built-in hospitals. In this study, we sampled two distinct seasonal solid-, liquid- and gaseous-state samples in a large occupied hospital, and mainly aim to study the temporal and spatial micro-ecology and antibiotic resistance gene (ARG) distribution patterns within hospital settings using culture-facilitated comparative metagenomics in combinations with other widely applied methods. Results: Hospital aerosol resistome showed concentration of 0.00042 copies per 16S rRNA gene which was comparable to that of drinking water (0.00024 copies/16S rRNA). Winter aerosols showed higher resistome concentration and exhibited similar distribution patterns among different departments; while evident microbial accumulation and stronger level of inter-species ARG exchange was observed in summer aerosol samples. Network analysis and cultural isolate whole genome sequencing results confirmed some of these exchanges were mediated via plasmids. Additionally, ARGs and microbial community source tracking results illustrated Outpatient hall could serve as a major resistome pollution source all year long. Conclusions: The state-of-art metagenomics analyses and culture facilitated sequencing with strict cutoff guarantee the result accuracy of resistome pattern observed in built-in hospital environment, and our novel genotype sharing network confirmed the plasmid-mediated transferring mechanism in hospital air for the first time. Overall, this study illustrated valuable and quality hospital aerosol dissemination patterns and our effort will encourage more metagenomics applications in hospital studies.