Background: There are no data available on the effects of intravenous (i.v.) methylcobalamin (Me-Cbl), the coenzymatically active form of vitamin B<sub>12</sub> that acts as a cofactor for methionine synthase in the conversion of total homocysteine (tHcy) to methionine, with or without oral folic acid (FA) supplementation, on fasting tHcy levels in hemodialysis (HD) patients. Methods: We performed a prospective randomized trial in which 62 chronic HD patients without previous vitamin supplementation were divided into four groups. Group A received Me-Cbl 500 µg twice/week plus FA 10 mg/day; group B received FA 10 mg/day alone; group C received no vitamin supplementation, and group D was on Me-Cbl 500 µg twice/week alone. Fasting tHcy, vitamin B<sub>12</sub>, serum (s) FA and erythrocytic (e) FA were measured predialysis before and after 4 months of therapy. Results: Final tHcy levels were significantly lower in group A (10.2 ± 3.1 µmol/l) compared to groups C (27.3 ± 9.7 µmol/l, p < 0.001) and group D (24.3 ± 11.8 µmol/l, p < 0.001) and similar to group B (11.2 ± 1.9 µmol/l, p = n.s.). Mean tHcy levels showed a significant decrease in group A from 22.5 ± 15.6 to 10.2 ± 3.1 µmol/l (p = 0.003) and in group B from 19.9 ± 4.0 to 11.2 ± 1.9 µmol/l (p = 0.012), while no significant changes were observed in groups C (25.9 ± 9.3 vs. 27.3 ± 9.7 µmol/l, p = n.s.) and D (26.6 ± 14.3 vs. 24.3 ± 11.8 µmol/l, p = n.s.). Conclusion: Oral FA (10 mg/day) supplementation appears to be an effective approach to normalize plasma tHcy in chronic HD patients; the addition of i.v. Me-Cbl (500 µg twice/week) to this regimen showed no benefit. Separately, FA corrected hyperhomocysteinemia (HtHcy), while Me-Cbl showed no change.