Background Volumetric modulated arc therapy (VMAT) adopted in post-mastectomy radiation therapy (PMRT) has the capacity to achieve highly conformal dose distributions. The research aims to evaluate the impact of positioning errors in the dosimetry of VMAT left-sided PMRT. Methods A total of 18 perturbations where introduced in 11 VMAT treatment plans that shifted the isocenter from its reference position of 3, 5, 10 mm in six directions. The thoracic wall and supraclavicular clinical target volumes (CTVs), the heart and the left lung dose volume histograms (DVHs) of 198 perturbed plans were calculated. The absolute differences ( increment ) of the mean dose (Dm) and DVH endpoints Vx and Dy (percentage volume receiving x Gy, and dose covering y% of the volume, respectively) were used to compare the dosimetry of the reference vs perturbed plans. Results Isocenter shifts in the anterior and lateral directions lead to maximum disagreement between the CTVs dosimetry of perturbed vs reference plans. Isocenter shifts of 10 mm shown a decrease of D95, D98 and Dm of 12.8, 18.0, and 2.9% respectively, for the CTVs. For 5 mm isocenter shifts, these differences decreased to 3.2, 5.2, and 0.9%, respectively, and for 3 mm shifts to 1.0, 1.7, and 0.6%, respectively. For the organs at risk (OARs), only isocenter shifts in the right, posterior and inferior directions worsen the plan dosimetry, nevertheless not negligible lung increment V20 of + 2.6%, and heart increment V25 of + 1.6% persist for 3 mm shifts. Conclusions Inaccuracy in isocenter positioning for VMAT left-sided PMRT irradiation may impact the dosimetry of the CTVs and OARs to a different extent, depending on the directions and magnitude of the perturbation. The acquired information could be useful for planning strategies to guarantee the accuracy of the treatment delivered.