Glucose intolerance and diabetes are becoming increasingly common in HIV-infected patients in the cART era. Many factors are associated with the development of diabetes in HIV-infected individuals who receive cART, one of which is the assumption of specific antiretroviral classes or agents. We describe a case in a 72-year-old Caucasian man with long-term HIV infection. We observed the development of unbalanced diabetes treated with insulin and metformin which improved when we replaced zidovudine with rilpivirine. This switch improved diabetes to such an extent that insulin suspension was required. In several countries zidovudine has long been used due to its low cost, although several side effects have been observed, especially in the long term. In this case, the switch to rilpivirine was shown to be able to improve the toxicity of zidovudine on glucose metabolism, representing a good option to be used.