We have compared the non-specific binding of unfractionated heparin (UFH) with that of low molecular weight heparin (LMWH) to plasma proteins both ex-vivo and in-vitro. Non-specific binding to plasma proteins was assessed by comparing the heparin levels measured as anti-factor Xa activity before and after the addition of low affinity heparin, which is essentially devoid of anti-factor Xa activity, in order to displace heparin bound to plasma proteins. For the ex-vivo studies, we compared the recovery of UFH and a LMWH (ardeparin) from the plasma of patients participating in a randomized trial of post-operative venous thrombosis prophylaxis. For the in-vitro studies, we compared the recovery of UFH and 4 different LMWHs when added to the plasma from healthy volunteers and from patients with suspected venous thromboembolic disease. The results indicate that the recovery of LMWH is much less affected by nonspecific binding to plasma proteins both ex-vivo and in-vitro. In addition, there are differences between the LMWHs with respect to their plasma protein-binding.