Hyperthermic isolated limb perfusion (ILP) with melphalan is well established as an effective form of treatment for recurrent melanoma confined to an extremity. High drug concentrations in the limb are readily achieved, without systemic side-effects. However, regional toxicity can lead to considerable morbidity and functional disturbance. This study was undertaken to evaluate factors which might contribute to acute regional toxicity following ILP. Melphalan concentrations in limb blood samples taken at regular intervals during 135 ILPs were measured by HPLC, allowing peak melphalan concentration and area under the curve (AUC) for each procedure to be determined. Acute regional toxicity associated with ILP was found to be significantly correlated with limb tissue temperatures > 40 degrees C, peak melphalan concentration and melphalan AUC, in decreasing order, but was not correlated with tourniquet time. Further studies are required to directly assess melphalan uptake by tumour tissue, and to relate this to both limb toxicity and tumour response.