The objectives of this study were to evaluate and identify determinants of health related quality of life (HRQoL) during pregnancy. Pregnant women (n = 245) completed questionnaires measuring: HRQoL (Short Form Health Survey SF-36), life stress, social support, sleep, and depressed mood in the third trimester. Demographics and medical variables were also collected. Compared to Canadian normative data, our sample scored significantly poorer on the following HRQoL domains: physical functioning, role limitations due to physical health problems, bodily pain, vitality, and social functioning. Multivariate linear regressions were used to model each of the SF-36 subscales. Experiencing sleep problems emerged as a significant determinant of poorer HRQoL in all domains, with the exception of emotional role. Higher depressed mood scores was independently associated with lower HRQoL in six of the eight domains, including bodily pain, general health, vitality, social functioning, emotional role, and mental health. Greater pregnancy-related anxiety was independently associated with lower scores on physical functioning and role limitations due to physical health problems. Women experience lower HRQoL during pregnancy, particularly in the physical domains. The importance of identifying and managing modifiable determinants early in pregnancy to enhance maternal health status is discussed.