Epidemiological and genetic correlates of Chlamydia trachomatis infection were examined prospectively in 124 male and 361 female adolescents at high risk for human immunodeficiency virus type 1 (HIV-1) infection. Seventy percent of subjects were African American, and 68% had HIV-1 infection. As expected, younger age (<17 years), multiple sex partners (≥2), and prior chlamydial infection predicted chlamydial infection during a 6-56-month follow-up period (P = .02, P = .02, and P = .03, respectively). Human leukocyte antigen (HLA) class II variant DQB1*06 (mostly *0602 and *0603) was associated with chlamydial infection (49% vs. 34%; adjusted relative odds [RO], 1.8; P = .005), as was HLA class I haplotype B*44-Cw*04 (10% vs. 4%; RO, 3.2; P = .009). DQB1*06 was found in 9 (75%) of 12 female adolescents with chlamydial pelvic inflammatory disease. In contrast, sex, ethnicity, and HIV-1 infection did not predict chlamydial infection. These findings suggest that antigen presentation in adaptive immune responses may serve as a major factor in effective control of C. trachomatis infection. The underlying mechanisms remain to be experimentally elucidated.