In 292 initially human immunodeficiency virus (HIV)-1-serodiscordant and cohabiting Zambian couples, HLA-DRB1 and -DQB1 variants were associated with HIV-1 transmission events during a 7-year follow-up period. Initially seronegative partners with either DRB1*0301-DQB1*0201 (relative hazard [RH], 1.60; P = .009) or DRB1*1503-DQB1*0602 (RH, 1.67; P = .03) showed accelerated seroconversion. Carriage of DRB1*1301 in initially seropositive partners led to delayed transmission of HIV to their spouses (RH, 0.54; P = .05). The combined groups of seroprevalent and seroincident partners (n = 433) also differed from those who remained seronegative (n = 151), with regard to 2 common haplotypes, DRB1*1302-DQB1*0604 (relative odds [RO], 0.28; P = .003) and DRB1*1503-DQB1*0602 (RO, 1.81; P = .02). Statistical adjustments for other host factors (age, sex, genital ulcer, and index partner's virus load) known to influence transmission of HIV-1 seldom altered the genetic relationships. Overall, associations of HLA class II polymorphisms with both HIV transmission and acquisition are not as readily interpretable as are effects reported for other loci.