In vivo delta-9-tetrahydrocannabinol (delta-9-THC) under short (10 and 50 mg/kg) and long term (10 mg/kg/day for 15 consecutive days) administration (i.p.) to adult male albino rats increased the mitochondrial swelling of hypothalamus, heart and liver. Similarly, in vitro treatment with delta-9-THC (2-8 micrograms/mg protein) produced a dose-dependent stimulation in the mitochondrial swelling of different tissues. Ca2+ ions (0.15 mM - 0.3 mM) increased the mitochondrial swelling. Calcium (0.3 mM)-induced stimulation of mitochondrial swelling was enhanced with delta-9-THC under both in vivo and in vitro conditions. Chaotropic agents e.g. KNO3 (100-200 mM) and KSCN (200-400 mM), decreased the mitochondrial swelling. Chaotropic (200 mM)-induced inhibitory effect in different tissues was reduced with delta-9-THC under in vivo and in vitro treatments. These results suggest that delta-9-THC, like calcium, stimulated the mitochondrial swelling, and that the action of delta-9-THC may be localized on the specific structures of the membrane which are sensitive to chaotropic agents.