The use of interferon-α and allogeneic stem cell transplant and more recently of tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with chronic myeloid leukemia (CML). We performed a population-based study of CML to evaluate relative survival (RS) trend by treatment eras. All instances of CML diagnosed between 1975 and 2009 reported in the Surveillance, Epidemiology and End Results databases were reviewed. The incidence of CML was 1.75/100 000 persons per year and increased with age. The incidence was highest in Detroit and lowest among Asians. The 5-year RS ratios increased from 0.26 in patients diagnosed in 1975-1989 to 0.36 in 1990-2000 and 0.56 in 2001-2009. There was a significant improvement in 5-year RS ratios in the 2005-2009 calendar period compared to the 2001-2004 period (p < 0.05), corresponding to the introduction of second-generation TKIs. Age was the most important prognostic factor for RS, but the improvement in 5-year RS ratios was observed in all age groups except the group aged < 15 years (p > 0.05), including adolescents and young adults and elderly patient groups. There are ethnic and geographic variations in the incidence of CML. The RS improved with each treatment era, with the greatest improvement in all age groups occurring during the TKI era.