The BRAFV600 mutation is present in ∼60% of melanomas and is translated into a continuous activated BRAF protein that dysregulates downstream mitogen-activated protein kinase (MAPK) signalling transduction, favouring melanoma proliferation, survival and progression [1,2]. The FDA approved the use of vemurafenib/PLX4032 specific inhibitor of BRAFV600 protein, for melanoma patients. Even though the use of vemurafenib increases the survival rate of patients, unfortunately a relapse of disease often occurs [3,4]. It is widely known that heme oxygenase-1 (HO-1) and its metabolites are involved in cellular redox homeostasis and counteract the oxidative stress generated by different stimuli. Notably, high levels of HO-1 in different types of tumor enhances survival, aggressiveness and poor outcome [5]. In this study, we investigated the involvement of HO-1 in the resistance and the angiogenic potential of BRAFV600E primary melanoma cells to the treatment with PLX4032. Primary melanoma cells (MeOV-1) were exposed to PLX4032 (10μM) for 24h and the involvement of HO-1 was studied by gene silencing. Experiments were conducted under standard cell culture conditions (air) and physiological and hypoxic oxygen levels (respectively 18kPa, 5kPa, 1kPa) in a Scitive workstation (Baker-Ruskin). Angiogenic potential was evaluated by seeding them on bovine aortic endothelium cells (BAEC) in Matrigel and treating them with conditioned medium derived from melanoma cells. An MTT assay showed that cell viability was reduced by 40% in cells exposed to PLX4032, with no differences observed under different oxygen levels. Under 18 kPa O2, PLX4032 increased HO-1 protein expression, whereas HO-1 induction was reduced at 5kPa and 1kPa O2. Interestingly, PLX4032 treatment completely abrogated HIF-1α expression in cells under 18kPa and 5kPa O2 but not under hypoxia. qPCR and immunoblotting analysis of Nrf2-dependent target genes shown that Nrf2 is not involved in the upregulation of HO-1. When BAEC seeded on Matrigel were treated with medium derived from MeOV-1 cells exposed to 10μM PLX4032, tube formation, branching and density were increased: when BAEC were treated with conditioned medium from MeOV-1 cells silenced for HO-1 and treated with PLX4032 the ability to form tubes was reduced. In conclusion, downregulation of HO-1 may provide a promising target to increase the efficacy of vemurafenib on BRAFV600E melanoma cells.