Maternal postpartum depression has a deleterious effect on the mother and child. The study aimed to assess the prevalence of postpartum depression (PPD) and its determinants, and to examine the relationship between PPD and health related quality of life (HRQOL) among women in Kuwait. A cross-sectional study was conducted in 18 randomly selected vaccination centers, where mothers visited these centers to vaccinate their children. Women who had live births within the last six months were eligible to participate in the study. However, women who: had any disabling condition, were under any psychiatric treatment, had stillbirths, or pregnant were excluded. Self-administered questionnaires including socio-demographic characteristics, recent obstetric history, the Edinburgh Postnatal Depression Scale, and the SF-12, were completed by 658 women with a response rate of 90.6%. The prevalence of PPD was 45.9% (CI: 42.1%-49.8%). Binary logistic regression analysis revealed that low educational level, unplanned pregnancy, no breastfeeding, and past history of PPD were significant determinants to PPD. Moreover, multiple linear regression analysis demonstrated a significant inverse association between PPD and HRQOL (overall, physical and mental health domains). One unit increase in PPD mean total score was associated with reduction in HRQOL overall, physical and mental health domains mean total scores by 1.35, 1.23, and 1.46 respectively. Appropriate measures should be implemented to prevent PPD and its deleterious effects both on mothers and children. Further research, particularly qualitative studies, to explore cultural correlates of PPD in Kuwait is needed.