To clarify the clinical and bacteriological correlates of urinary-tract infection (UTI) due to Escherichia coli O15:K52:H1, during a 1-year surveillance period we prospectively screened all 1, 871 significant E. coli urine isolates at the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, for this serotype and assessed the epidemiological features of community-acquired UTI due to E. coli O15:K52:H1 versus other E. coli serotypes. We also compared the 25 O15:K52:H1 UTI isolates from the present study with 22 O15:K52:H1 isolates from other, diverse geographic locales and with 23 standard control strains (8 strains from the ECOR reference collection and 15 strains of nonpathogenic O:K:H serotypes) with respect to multiple phenotypic and genotypic traits. Although E. coli O15:K52:H1 caused only 1.4% of community-acquired E. coli UTIs during the surveillance period, these UTIs were more likely to present as pyelonephritis and to occur in younger hosts, with similar risk factors, than were UTIs due to other E. coli serotypes. Irrespective of geographic origin, E. coli O15:K52:H1 strains exhibited a comparatively restricted repertoire of distinctive virulence factor profiles (typically, they were positive for papG allele II, papA allele F16, and aer and negative for sfa, afa, hly, and cnf1), biotypes, ribotypes, and amplotypes, consistent with a common clonal origin. In contrast, their antimicrobial resistance profiles were more extensive and more diverse than those of control strains. These findings indicate that E. coli O15:K52:H1 constitutes a broadly distributed and clinically significant uropathogenic clone with fluid antimicrobial resistance capabilities.