We investigated the effect of 2‐methyl‐arachidonyl‐2′‐fluoro‐ethylamide (Met‐F‐AEA), a stable analog of the endocannabinoid anandamide, on a rat thyroid epithelial cell line (FRTL‐5) transformed by the K‐ras oncogene, and on epithelial tumors derived from these cells. Met‐F‐AEA effect in vivo was evaluated in a nude mouse xenograft model, where K‐ras‐transformed (KiMol) cells were implanted subcutaneously. Met‐F‐AEA (0.5 mg/kg/dose) induced a drastic reduction in tumor volume. This effect was inhibited by the CBi receptor antagonist SR141716A (0.7 mg/kg/dose) and was accompanied by a strong reduction of K‐ras activity. Accordingly, KiMol cells and tumors express CB₁ receptors. Met‐F‐AEA inhibited (IC₅₀ ~5 μM) the proliferation in vitro and the transition to the S phase of KiMol cells and it reduced K‐ras activity; these effects were antagonized by SR141716A. Met‐F‐AEA cytostatic action was significantly smaller in nontransformed FRTL‐5 cells than in KiMol cells. Met‐F‐AEA treatment exerted opposite effects on the expression of CB1 receptors in KiMol and FRTL‐5 cells, with a strong up‐regulation in the former case and a suppression in nontransformed cells. The data suggest that: 1) Met‐F‐AEA inhibits ras oncogene‐dependent tumor growth in vivo through CB1 cannabinoid receptors; and 2) responsiveness of FRTL‐5 cells to endocannabinoids depends on whether or not they are transformed by K‐ras.