Cervical cancer is one of the most common malignancy worldwide. Recent studies have shown that HIV-protease inhibitors (HIV-PIs), widely used in highly antiretroviral therapy, led to a reduced incidence and regression of HIV-associated tumors in infected patients. Evidences indicate that this antitumor effect is not only the result of drug-mediated HIV suppression and immune reconstitution, but also of direct anti-angiogenic and anti-tumor actions. Herein we sought to evaluate whether HIV-PIs could impair events leading to cervical cancer employing a mouse model of spontaneous cervical cancer, K14-HPV/E2. We performed a prevention-intervention trial aimed to prevent or regress tumor progression and angiogenesis by treating mice with Indinavir, Saquinavir and Ritonavir. HIV-PIs indirectly inhibited tumor growth and incidence by exerting an antiangiogenic effect and, consequently, by inducing tumor apoptosis. We further performed a regression trial, starting treatments when the mice had invasive tumors, to evaluate if HIV-PIs were able to regress or stabilize tumor progression. Interestingly HIV-PIs dramatically reduced tumor burden and invasiveness by increasing collagen-IV expression compared to controls. Remarkably, in both treatments, HIV-PIs completely inhibited matrix metalloprotease (MMP)-9 activity in tumors compared to controls. Since MMP-9 is involved in the mobilization of VEGF-A from the matrix, we evaluated the formation of VEGF-A-VEGR-2 complex in tumor vessels. Of note HIV-PIs strongly reduced the amount of VEGF bound to its receptor VEGFR2, in parallel to a dramatic reduction in MMP-9 activity, suggesting that HIV-PIs, by targeting MMP-9, impair the VEGF-A pathway and therefore inhibit tumor angiogenesis. We conclude that HIV-PIs have anti-angiogenic and anti-tumor effects on cervical carcinogenesis unrelated to their antiviral activity and that these drugs could represent new antiangiogenic targets that can be easily transferred to the clinic.