Intentional drug overdose (IDO) has been linked with marked increases in premature mortality risk due to suicide, accidents and other causes, yet little is known about how case fatality risk varies according to the type of drug/s taken. This study aimed to examine the incidence of IDO, to identify the predictors of fatal IDO and to establish which drugs are linked with greater risk of a fatal outcome. Methods Data from the National Self-Harm Registry, and the National Drug-Related Deaths Index, 2007–2014, were used to calculate incidence, examine overdose characteristics and estimate case fatality risk ratios. Results We examined 63,831 non-fatal and 364 fatal IDOs (incidence: 148.8 and 1.01 per 100,000 respectively). Compared to non-fatal IDOs, fatal cases were more often male (55.2% vs. 42.0%), older in age (median 44 vs. 35 years), and more frequently involved multiple drugs (78.3% vs. 48.5%). Tricyclic antidepressants were associated with a 15-fold increased risk of death and opioids a 12-fold increased risk, relative to the reference category (non-opioid analgesics). While the risk of fatal outcome was higher for males than females, the elevation in risk was greater in females when tricyclic antidepressants or opioids were taken. Conclusion Male gender, increasing age and multiple drug use were associated with fatal IDO outcome. Tricyclic antidepressants and opioids were associated with a significantly increased risk of death following intentional overdose. Clinicians need to consider the case fatality risk of drugs when determining treatment for patients at risk of or those who have previously harmed themselves.