The aim of this study was to evaluate the relationship of stressful events (SE) with the onset and outcome of Graves' disease (GD). Over a period of 21 years, we enrolled 58 consecutive patients in whom at least one SE had occurred ≤12 months before the onset of GD. Patients were treated with antithyroid drugs (ATD) for ≥12 months and followed up for ≥5 years after ATD withdrawal. We divided patients in three groups: REM (who reached remission; 25.9%); EXA (who experienced ≥1 exacerbation during ATD; 10.3%); and REL (who experienced ≥1 relapse after ATD withdrawal; 63.8%). The average age at onset was similar in the three groups. All males aged ≤25 years at GD onset relapsed at least once; no patient aged ≥51 years at GD onset relapsed ≥2 times. All patients who exacerbated or relapsed had at least one SE preceding each exacerbation or relapse. The time lag between SE and onset of GD (19.3±11.9 weeks) correlated with the age at onset (r=0.292, P=0.0002), particularly in the REL group (r=0.346, P=0.001). Overall, EXA and REL patients experienced more SE than REM patients (P=0.0002 and P=0.003, respectively). In the REL group, the overall number of SE was correlated with the number of relapses (r=0.486, P<0.0001). There exist GD patients who are prone to develop hyperthyroidism and its recurrences when exposed to SE. They are relatively young; the younger these patients are, the shorter is the time lag between SE and the onset of hyperthyroidism.