OBJECTIVE The aim of this study was to characterise rates of late mortality and second cancers in an Australian cohort of childhood cancer survivors and compare these to rates observed in the New South Wales population. DESIGN, SETTING AND PARTICIPANTS Records for 896 childhood cancer survivors treated at the Sydney Children's Hospital between 1972 and 1999 were linked to the National Death Index and NSW Central Cancer Registry to identify deaths and notifications of second cancers. Survivors were defined as those alive for at least 5 years after diagnosis and were followed until death or 31 December 2004, whichever occurred first. MAIN OUTCOME MEASURES Standardised mortality ratios (SMRs) and standardised incidence ratios (SIRs) were used as measures of relative risk. A Cox proportional hazard model was used to quantify the influence of demographic and disease-related characteristics on the risk of death and second cancers. RESULTS The SMR and SIR were 7.46 and 4.98 times higher, respectively, among cancer survivors relative to the NSW population. Relative mortality was highest in survivors of soft-tissue sarcoma (SMR, 18.95 [95% CI, 6.88-40.81]) and central nervous system (CNS) malignancies (SMR, 16.78 [95% CI, 7.62-31.64]). The leading causes of death included recurrence of the primary childhood cancer (55%) and second cancers (12%), as well as treatment-related complications (17%) The most frequently observed second cancers were bone and thyroid cancers, melanoma, and CNS malignancies, and second cancers were most common among survivors of leukaemia, soft-tissue sarcoma and Hodgkin's lymphoma. CONCLUSIONS Compared with the general population, survivors of childhood cancer in Australia are at increased risk of late mortality and second cancers. These findings highlight a continuing need to assess health issues faced by childhood cancer survivors and develop strategies to minimise the adverse outcomes associated with treatment for childhood cancer.