Difructose anhydride III (DFAIII) is an indigestible disaccharide and has been shown to enhance iron absorption in animal studies; however, the effect has not been investigated in anemic subjects. We investigated the efficacy of co-administration of DFAIII with water-insoluble iron in the treatment of iron deficiency anemia in Vietnamese women. One hundred sixty-eight moderately anemic women (80 g/L<hemoglobin (Hb)<120 g/L) participated in a double-blinded, placebo-controlled study with daily supplementation of iron for 6 mo. The volunteers were randomly assigned into four groups, i.e., Group A: received 15 mg Fe as ferric pyrophosphate; Group B: received 15 mg Fe as ferric pyrophosphate and 1.25 g DFAIII; Group C: received 15 mg Fe as ferrous sulfate; Group D: received a placebo. Hb and iron status were measured at baseline and after 2, 4 and 6 mo of intervention. The ratio of transferrin receptor to ferritin was used to estimate stored and functional body iron (BI). One hundred sixteen (69.0%) women completed the trial. After 6 mo, mean (+/-SE) Hb concentration was higher in Group A (121.6+/-1.7 g/L), Group B (126.4+/-1.5 g/L) and Group C (126.8+/-1.6 g/L) compared to Group D (107.0+/-1.7 g/L, p<0.0001). Mean change in BI was twofold greater in Group B (5.0+/-0.5 mg/kg) than that in Group A (2.5+/-0.6 mg/kg, p=0.008). The percentage of anemia was significantly reduced in Group B (18.8%) compared to Group D (95.8%, p<0.0001) and Group A (39.1%, p=0.033). Co-administration of DFAIII enhances Hb concentration and iron stores more than single administration of water-insoluble iron in anemic Vietnamese women.