HIV risk is determined by the interaction between social and individual risk factors, but information about such factors among Nepalese women is not yet understood. Therefore, to assess the risk factors and vulnerability of the wives of Nepalese labor migrants to HIV infection, we conducted a mixed-methods study in which a descriptive qualitative study was embedded within a case-control study. We interviewed 224 wives of labor migrants in the case-control study, and conducted two focus group discussions (n = 8 and 9) in the qualitative study. We found that illiteracy, low socio-economic status and gender inequality contributed to poor knowledge and poor sexual negotiation among the wives of labor migrants and increased their risk of HIV through unprotected sex. Among male labor migrants, illiteracy, low socio-economic status, migration to India before marriage and alcohol consumption contributed to liaisons with female sex workers, increasing the risk of HIV to the men and their wives through unprotected sex. Both labor migrants and their wives feared disclosure of positive HIV status due to HIV stigma and thus were less likely to be tested for HIV. HIV prevention programs should consider the interaction among these risk factors when targeting labor migrants and their wives.