The aim of our study was to study the changes in the clinical picture and outcomes of granulomatosis with polyangiitis (Wegener's) (GPA) over 40 years. Two hundred and forty-two consecutive patients with GPA were distributed into retrospective (1970-2003) and prospective (2004-2012) cohorts. Anti-neutrophil cytoplasmic antibodies were present in 82.6 % of patients. In 78.0 % of patients, diagnosis was confirmed histologically. We compared the clinical features of GPA and the incidence of the major and minor relapses and mortality in the two cohorts. The majority of patients in both cohorts had generalized GPA that involved upper respiratory tract (retrospective 89.5 % vs prospective 82.85 %), kidneys (60.5 vs 50.8 %) and lungs (64.0 vs 52.3 %). The total duration of follow-up in the retrospective and prospective cohorts was 468 and 397 patients-years, respectively. In the prospective cohort, we found trend to lower incidence of relapses (54.2 vs 66.2 per 100 patient-year; p = ns; odds ratio 0.82; 95 % CI 0.53-1.21) and significantly lower mortality (4.3 vs 7.9 per 100 patient-year; p = 0.04; odds ratio 0.54; 95 % CI 0.31-0.94). The leading causes of death in the retrospective cohort were lung disease (37.8 %), complications of immunosuppressive treatment (35.1 %) and kidney failure (13.5 %). In the prospective cohort, patients rarely died from terminal uraemia and pulmonary complications (0.0 and 17.6 %) while the proportion of cardiovascular events and complications of the immunosuppression as the causes of death increased (29.4 and 47.1 %). Modern treatment apparently reduced the incidence of relapses and mortality and modified the causes of death in the GPA patients.