Background: Hyperhomocysteinaemia is an independent cardiovascular risk factor in patients with renal disease. The current study aimed to determine the effect of intravenous N-acetylcysteine on plasma homocysteine levels when administered during haemodialysis in patients with end-stage renal failure. Patients and methods: Sixty patients with end-stage renal failure were randomised to receive a 4-hour intravenous infusion of N-acetylcysteine or placebo during a 4-hour haemodialysis session. Plasma homocysteine levels were measured before and after haemodialysis. Haemodynamic parameters, including pulse pressure, were also measured. Results: After haemodialysis in the placebo treatment group, plasma homocysteine was reduced by 23.7% from the pre-dialysis level, whereas patients treated with N-acetylcysteine exhibited an 88.3% decrease (p < 0.001). Reduction of plasma homocysteine concentration was significantly correlated with a reduction of pulse pressure (p = 0.001). A 10% decrease in plasma homocysteine concentration was associated with a 1.45mm Hg decrease in pulse pressure. Conclusions: Intravenous administration of N-acetylcysteine during haemodialysis normalises plasma homocysteine concentration, and this is associated with improved pulse pressure in patients with end-stage renal failure. Intravenous administration of N-acetylcysteine during haemodialysis may be a promising approach to help reduce cardiovascular risk in this vulnerable group of patients.