Background: Deleterious effects of high levels of free fatty acids (FFA) lead to a phenomenon known as lipotoxicity, associated with insulin resistance and beta pancreatic cell damage, key events in development of type 2 diabetes (T2D). Lipotoxicity has been associated with cellular oxidative stress and beta-cell apoptosis, however, many aspects of cellular mechanisms involved remains to be defined. Caveolin-1 (CAV1) is a membrane protein normally present in beta pancreatic cells, but its role in these cells has been poorly explored. We previously reported that the expression of the membrane protein CAV1 promotes palmitate-induced apoptosis in vitro in a mouse beta cell line. However, remains to be elucidated if this phenomenon is relevant in vivo, in a whole organism subjected to lipotoxic conditions induced by a high fat diet (HFD). Our aim was to elucidate whether in mice lacking CAV1 expression, their pancreatic islets present a greater resistance to lipotoxic effects of a HFD. Materials and methods: We used C57BL6J WT mice and K.O. mice lacking expression of Caveolin-1 (CAV1 K.O. mice). Mice were anesthetized by an intraperitoneal injection of ketamine/xylazine (100/10mg/kg) before surgery. The pancreases were removed by laparotomy. We evaluated the FFA, triglycerides and insulin levels in blood in fasting conditions, oral glucose tolerance test (GTT), carbonylated proteins in serum and C-peptide in WT mice and CAV1-K.O. mice exposed to HFD 60% for 3 months, and they were compared with mice fed with a control diet (CD). Also, the presence of apoptosis was evaluated by TUNEL staining in beta pancreatic islets from K.O. and WT mice. All the experiments had groups of animals >5 and <8 individuals. Results: We found that HFD WT mice, showed higher levels of triglycerides (p<0.05), cholesterol (p<0.01), FFA (N.S.), insulin (p>0.05) and carbonylated proteins (p<0.001) compared to CD WT mice. CAV1 K.O. mice showed an altered profile even in C.D, but there were not significant differences compared with HFD. The levels of FFA were high with C.D., but the HFD did not change these levels significantly. The HFD worsened the response to GTT in WT mice, increasing AUC (p<0.01). In contrast, K.O. mice presented an altered GTT with C.D., but the HFD did not make it significantly worse. Interestingly, the C-peptide levels were significantly higher in K.O. mice fed with HFD compared with K.O. CD (p<0.001) and also even with WT HFD. Importantly, islets from HFD K.O. mice showed lower levels of apoptosis compared with HFD WT mice, evidenced by TUNEL staining (9.6 vs 15.5% TUNEL positive nuclei). Conclusion: Our results suggest that their pancreatic islets were more resistant to HFD deleterious effects over beta cells, accordingly with our previous results in vitro. We think that this could be a very interesting aspect of beta cell biology that could help to identify targets for advanced therapies in preventing T2D.