The high frequency of fluoroquinolone resistance inEscherichia coliis a feature of clinical bacteriology in China, where the molecular epidemiology and genetic characteristics of this resistance in county hospitals remain unclear. A total of 590 nonduplicateE. coliisolates from 30 county hospitals located across seven Chinese regions were examined for plasmid-mediated quinolone resistance (PMQR) genes and mutations in quinolone resistance-determining regions (QRDRs). Multilocus sequence typing (MLST) and phylogenetic analysis of fluoroquinolone-resistant isolates were used to determine their genetic relatedness. The ciprofloxacin resistance rate of community-onsetE. coliwas 51.2%, and at least one PMQR gene was carried by 220 (37.3%) isolates. These includedqnr(3.7%),aac(6′)-Ib-cr(19.7%),qepA(14.4%), andoqxAB(3.8%). Two noveloqxBmutants were identified and namedoqxB20andoqxB29. From 60 sequence types (STs) isolated, 5 novel STs (ST4499 to ST4503) were identified. ST1193 (7.9%) was the second most abundant ST among fluoroquinolone-resistant isolates (ST131 was the most common, with 14.6%), and this is the first report of it in China. This is also the first report of ST2115 and ST3014 isolates from human samples. Ciprofloxacin-resistantE. coliisolates fell mainly into phylogroups B2 and D. The rates of fluoroquinolone resistance and the prevalence of PMQR genes in community-onsetE. coliisolates from Chinese county hospitals were high. The wide-ranging molecular epidemiology ofE. coliisolates from scattered locations across China indicates that fluoroquinolone resistance evolved from different sources.