Decreased expression of heparan sulphate has been shown in the glomerular basement membrane of patients with over diabetic nephropathy. Low- molecular-weight heparin (LMWH) is a highly sulphated glycosaminoglycan with strong structural and functional similarities to heparan sulphate. In a first study, we set out to assess if LMWH could decrease the urinary albumin excretion rate (AER) in diabetic patients with over nephropathy. Six patients entered a randomized, double-blind, placebo-controlled crossover study with treatment episodes of 1 month, separated by a 1-month wash-out. Patients self-administered prefilled syringes with either placebo or LMWH (enoxaparin 40 mg/0.4 ml) at bedtime. Baseline AER levels before either treatment period were similar. In contrast to placebo, AER significantly decreased from 447 (181-1102) to 295 (100-873) micrograms/min after 1 month treatment with LMWH (P < 0.05). Compared to placebo, the effect of LMWH did not reach statistical significance in these six patients after 1 month treatment (P = 0.16). Haemodynamic variables including glomerular filtration rate and filtration fraction did not change during enoxaparin treatment. We observed a favourable effect on AER during LMWH treatment in diabetic patients with over nephropathy. These data suggest that long-term treatment trials in a larger group of patients may potentially demonstrate a new therapeutic option for patients with over diabetic nephropathy.