Campylobacterspecies are zoonotic pathogens, as well as the prevalent cause of foodborne bacterial gastroenteritis. The spread of antimicrobial-resistant strains poses a serious threat to global public health and attracts attention worldwide, but information about clinicalCampylobacteris relatively limited compared to isolates from food and animals. The current study illustrated the prevalence and antimicrobial resistance profiles ofCampylobacter jejuniandCampylobacter coliisolates collected from a consecutive surveillance program between 2012 and 2019 in Shanghai, China, using antimicrobial susceptibility testing and whole-genome sequencing. Among the 891Campylobacterstrains (761C. jejuniand 130C. coli) isolates collected, high portions above 90% of resistance to ciprofloxacin, nalidixic acid, and tetracycline were observed for bothC. jejuniandC. coli. The most common MDR profiles represented byC. jejuniandC. coliwere combination of ciprofloxacin, tetracycline, florfenicol and nalidixic acid (5.39%), and azithromycin, ciprofloxacin, erythromycin, gentamicin, tetracycline, clindamycin, nalidixic acid (28.46%), respectively. The erythromycin resistance ofC. coli(59.23%) is higher thanC. jejuni(2.50%). A total of 76 erythromycin resistant isolates (16C. jejuniand 60C. coli) were sequenced using Illumina platform for determining the genotypes, antimicrobial resistance patterns and phylogeny analysis. Multilocus sequence typing (MLST) analysis showed a high genetic diversity with 47 sequence types (STs), including 4 novel alleles and 12 new STs. The most abundant clonal complexes (CCs) were CC-403 (31.25%) and CC-828 (88.33%) forC. jejuniandC. coli, respectively. Among the 76 erythromycin-resistant isolates, mutation A2075G in 23S rRNA anderm(B) gene were detected in 53.95 and 39.47%, respectively. Theerm(B) gene was identified exclusively in 30C. coliisolates. All theseerm(B) positive isolates were multi-drug resistant. Furthermore, comparison of theerm(B)-carrying isolates of multiple sources worldwide demonstrated the possibility of zoonotic transmission oferm(B) inCampylobacter. These findings highlight the importance of continuous surveillance of erythromycin resistance dissemination inCampylobacterwhich may compromise the effectiveness of antimicrobial therapy.