The hypothesis was tested that the additional dietary uptake of n-3 fatty acids, in particular of DHA and 5-methyltetrahydrofolate (5-MTHF), during the second half of pregnancy would influence proliferation and apoptosis in the full-term human placenta. The diets of pregnant women from Spain (n 55) were supplemented with modified fish oil and/or 5-MTHF or placebo, and assigned in a random, double-blind manner to one of the four groups. Immunohistochemistry and immunoblotting were used to detect placental proliferation and apoptosis with monoclonal antibodies for key proteins that reflected the extent of both processes: proliferation cell nuclear antigen (PCNA), p53, cytokeratin 18 neoepitope. The PCNA level in the fish oil/5-MTHF-treated group was higher by 66 % (P < 0.05) than that of the placebo group, whereas the levels of p53 and cytokeratin 18 neoepitope were unaffected by treatment. PCNA expression was altered only in the trophoblast compartment (placebo 11.1 (se 0.5) % v. combination 21.5 (se 1.2) %; P < 0.05), whereas the proportion of nuclei stained in endothelial and other stromal cells was similar in the placebo and combined treatment groups. No correlation was found between fish oil or 5-MTHF supplementation and the levels of the proteins. The present data suggest that supplementation with fish oil and/or 5-MTHF had no effect on the parameters reflecting placental proliferation and apoptosis. A defined combination of DHA and 5-MTHF may, however, affect placental proliferation.