Recurrent Chlamydia trachomatis infections are common among sexually active women. Although recurrences with a new chlamydial serovar indicate reinfection, same-serovar recurrences may be due to persistence. Because persistence has important implications for pathogenesis and patient management, we identified 552 women with >3 recurrences over 2 years. Among these, 130 women (24%) had same-serovar recurrences; 58 (45%) were C class serovars (odds ratio, 2.4; 95% confidence interval, 1.7-3.5; P<.0001). Forty-five isolates from 7 women with 3-10 repeated, same-serovar infections over 2-5 years were studied. As determined by omp1 genotyping, 4 women had identical genotypes at each recurrence; 2 women had 1 or 2 amino acid changes following treatment, and one was persistently infected with a unique genotype, Ja. Many intervening culture-negative samples were positive when tested by ligase chain reaction, which suggests persistence. These data demonstrate that cervical infections with C class serovars can persist for years and may have specific biologic properties that allow for modulation of the major outer membrane protein in response to immune selection.