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Streptomycin is considered to be one of the effective antibiotics for the treatment of plague. In order to investigate the streptomycin resistance of Y. pestis in China, we evaluated streptomycin susceptibility of 536 Y. pestis strains in China in vitro using the minimal inhibitory concentration (MIC) and screened streptomycin resistance-associated genes (strA and strB) by PCR method. A clinical Y. pestis isolate (S19960127) exhibited high-level resistance to streptomycin (the MIC was 4,096 mg/L). The strain (biovar antiqua) was isolated from a pneumonic plague outbreak in 1996 in Tibet Autonomous Region, China, belonging to the Marmota himalayana Qinghai–Tibet Plateau plague focus. In contrast to previously reported streptomycin resistance mediated by conjugative plasmids, the genome sequencing and allelic replacement experiments demonstrated that an rpsL gene (ribosomal protein S12) mutation with substitution of amino-acid 43 (K43R) was responsible for the high-level resistance to streptomycin in strain S19960127, which is consistent with the mutation reported in some streptomycin-resistant Mycobacterium tuberculosis strains. Streptomycin is used as the first-line treatment against plague in many countries. The emergence of streptomycin resistance in Y. pestis represents a critical public health problem. So streptomycin susceptibility monitoring of Y. pestis isolates should not only include plasmid-mediated resistance but also include the ribosomal protein S12 gene (rpsL) mutation, especially when treatment failure is suspected due to antibiotic resistance. Author summary: The plague natural foci are widely distributed in the world, and correspondingly, the plague still poses a significant threat to human health in some countries with endemic plague foci. Streptomycin is used as the first-line treatment against plague in many countries for the antibiotic is considered to be one of the effective antibiotics, particularly for the treatment of pneumonic plague. The resistance to streptomycin had been reported in Y. pestis strains from Madagascar in previous studies. In this study, we reported the high-level resistance to streptomycin in a clinical isolate of Y. pestis from a pneumonic patient in Tibet Autonomous Region, China, and a novel mechanism of streptomycin resistance, i.e. mutation in the rpsL gene were identified. The knowledge acquired about streptomycin resistance in Y. pestis will remain of great practical value. For the emergence of resistance to streptomycin in Y. pestis would render the treatment failure, thus corresponding antibiotic monitoring should be routinely carried out in countries threatened by plague. In addition, based on our further understanding about streptomycin resistance of Y. pestis isolates, such monitoring should not only include plasmid-mediated resistance but also include the ribosomal protein S12 gene (rpsL) mutation in Y. pestis isolates. [ABSTRACT FROM AUTHOR]