BACKGROUND Anemia in pregnancy is highly prevalent among antenatal clinic attendees in Enugu, Nigeria despite the practice of routine iron supplementation in pregnancy. The major problem with iron supplementation in pregnancy is compliance, and this may be a potential driver to the persistent high prevalence of anemia in this population. OBJECTIVE To find out the compliance rate and determinants of compliance to iron supplementation among pregnant women in Enugu, southeastern Nigeria. METHODS This was a questionnaire-based cross-sectional study of eligible pregnant women receiving antenatal care at the University of Nigeria Teaching Hospital (UNTH), Ituku/Ozalla, Enugu, Nigeria between April 1, 2012 and January 31, 2013. RESULTS The knowledge of iron supplementation was 76.3% ( n = 302), however, the compliance rate was 65.9% ( n = 261). Tertiary level of education and high social class were factors significantly associated with compliance to iron supplementation after adjusting for other factors in the binary logistic regression analysis ( P < 0.05). The major barriers to compliance to iron supplementation included gastrointestinal side effects of iron supplements (41.7%), non-affordability of iron supplements (28.3%), and forgetfulness (15.0%) among the antenatal mothers. CONCLUSIONS The compliance rate of 65.9% for iron supplementation by pregnant mothers in Enugu can further be improved by providing the drug free of charge in the short term and improvement in education and socioeconomic class of the populace in the long run.