Abstract:[Objective] The aim of this research is to study the temporal and spatial changes of atypical virulence genes and drug resistance of the marine fish pathogen Photobacterium damselae in South China, and analyze the potential environmental factors driving the change of virulence and drug resistance in P. damselae, and consequently provide suggestions for disease prevention and control caused by P. damselae. [Methods] Based on PCR and Kirby-Bauer diffusion method, we analyzed the presence of 5 atypical virulence genes and the resistance to 15 tested antibiotics of 35 P. damselae strains isolated from diseased marine fishes in South China coastal area. [Results] The results show that:(1) 19 strains contained 1-2 atypical virulence genes, particularly, the detection rate of hlyA and vvh were higher than 20%; (2) 27 resistance types were observed in these 35 strains, the multi-antibiotic resistance index of was 0.00-0.67 with the multi-antibiotic resistance rate (one strain shows resistance to more than 3 antibiotics) up to 60.00%. Therein, more than 50% strains showed resistance to vancomycin, amoxicillin, midecamycin and rifampin, but less than 10% strains resisted to gentamicin, norfloxacin, ciprofloxacin, chloramphenicol and florfenicol; (3) The atypical virulence gene contents and drug resistance were marginally increased with the year grows, and more/stronger in Hainan than in Guangdong. Further, the richness of resistance types, multi-antibiotic resistance rate, the most resistant number in one strain, and multi-antibiotic resistance index were observed higher/more in Hainan (1.00, 69.23%, 10, 0.32, respectively) than in Guangdong (0.82, 54.55%, 9, 0.25, respectively). [Conclusion] These results indicated that atypical virulence genes probably be transferred into P. damselae by horizontal gene transfer and the variation of virulence and drug resistance of P. damselae isolated form Hainan and Guangdong are mainly affected by temperature and antibiotic pollution.