BACKGROUND: Elevated plasma total homocysteine (tHcy) concentration is an emerging independent risk factor for hypercoagulability states and cardiovascular diseases. Many disease states and various drug treatment regimens are known to affect plasma tHcy concentration. OBJECTIVE: To examine the effect of short-term treatment with the low-molecular-weight heparin enoxaparin on plasma tHcy concentrations. METHODS: A prospective study was conducted in an outpatient anticoagulation clinic set in a tertiary care referral medical center. Subjects included twenty-four consecutive patients treated with warfarin who were scheduled for short-term enoxaparin treatment. Fasting plasma tHcy concentrations were measured before and after 3 days of enoxaparin treatment in patients who began short-term therapy with enoxaparin because of temporary inadequate anticoagulation (international normalized ratio <1.5). The main outcome measures were the difference in tHcy concentration between baseline and after enoxaparin treatment. RESULTS: tHcy plasma concentrations decreased in most patients (n = 21), did not change in 2, and increased in 1 patient after 3 days of enoxaparin treatment. The decline of tHcy was statistically significant: from 9.8 ± 3.4 to 7.6 ± 2.6 μmol/L (mean ± SD; p < 0.005). This decline was more prominent in patients with baseline tHcy plasma concentrations above the normal range compared with patients with normal baseline concentrations. Six patients in whom a third sample was obtained 15-30 days after the last enoxaparin injection developed decreased mean tHcy plasma concentrations: from 9.1 ± 3.0 μmol/L at baseline to 6.4 ± 2.0 μmol/L on day 3 and further to 5.7 ± 1.8 μmol/L on days 15-30. No relation was found between age, gender, treatment indication, and average weekly dose of warfarin to the presence or magnitude of tHcy plasma concentration decline. CONCLUSIONS: Short-term treatment with enoxaparin reduces plasma tHcy concentrations. Further studies are needed to clarify the mechanism and the clinical significance of enoxaparin's effect.