A melanoma cell line (M14) was used in order to investigate the effect of hyperthermia on the mechanisms of interaction between liposomes and cultured cells. The treatment was performed by adding different concentrations of multilamellar liposomes (L-alpha-dipalmitoylphosphatidylcholine, stearylamine and cholesterol in the ratio 7:2:1) to cell cultures which were then incubated at 37.0 or 41.5 degrees C for 2 h. The damage induced by liposome treatment in normothermia or hyperthermia was evaluated by determining cell survival and by electron microscopy. When different concentrations of liposomes were used, a dose-dependent impairment of cell survival was observed. An enhancement of the cytotoxic effect was observed when the treatment was performed at 41.5 degrees C. This effect went on even after 24 h from the end of the treatment, but the difference between cells treated in normothermia and hyperthermia was remarkably reduced. The mechanism of the liposome-plasma membrane interaction has been investigated by electron microscopy. Our observations demonstrated that the outer bilayer of the multilamellar liposomes was capable of fusing with the plasma membrane, inducing changes in its fluidity and molecular organization. Following this process the inner liposomal bilayers entered the cell. These effects seemed to be favoured when the treatment was performed under mild hyperthermic conditions, accounting for the synergic cytotoxic action displayed by the liposome-hyperthermia association.