Multifocal progressive leukoencephalopathy (PML) is associated with JC virus (JCV) seropositivity, past immunosuppression, and natalizumab treatment for two years or more. The aim of our study was to investigate the rate of treatment discontinuation after stratifying for the three risk factors in a group of 104 natalizumab-treated patients with relapsing–remitting multiple sclerosis. We investigated JCV serological status in our population. We then divided patients into groups according to their PML risk. Treatment indication was reassessed. Of the patients, 64 (61.5%) were JCV seropositive. Amongst seropositive patients on natalizumab for 2 years or more, 10 had received immunosuppression (group A), and 38 had not (group B). After an informed and shared decision-making process, 6/10 (60%) from group A compared with 9/38 (23.7%) from group B discontinued treatment ( p=0.027). In groups A and B, discontinuation also depended upon doctors’ views ( p=0.019, group A; p=0.010, group B) and clinical outcomes ( p=0.021, group A). No-one from low–intermediate risk groups discontinued. The decision to discontinue natalizumab treatment is complex, even when clear PML risk rates are described. Clinical outcomes and doctors’ idiosyncrasies play a crucial part in patients’ final choice.