BACKGROUND US opioid overdose death rates have increased between 2000 and 2014. While, the increase in prescription opioid use has been linked to the increase in heroin use, there are reasons to view this relationship as a partial explanation for the recent increase in heroin-related harms. This study documents the differences in trends in prescription opioid overdose-related (POD) and heroin overdose-related (HOD) hospitalizations. METHODS Data come from the National Inpatient Sample (NIS) for the years 2000 through 2014. POD and HOD hospitalizations were abstracted from ICD-9 codes. Rates of POD and HOD by census region and census division were constructed along with separate rates for age and race. Regression analysis analyzing trends across region were estimated along with graphs for documenting differences in POD and HOD rates. RESULTS POD hospitalization rates were highest in the South and lowest in the Northeast. HOD hospitalization rates were highest in the Northeast region and grew the fastest in the Midwest. There was statistically significant heterogeneity in HOD trends but not POD trends across the four regions between 2000 and 2014. Between 2012 and 2014 POD rates decreased in eight of the nine census divisions, with only New England showing an increase. HOD hospitalization rates increased in all nine census divisions between 2012 and 2014. Both POD and HOD rates show different demographic patterns across the nine census divisions. CONCLUSION Comparing POD and HOD hospitalization trends reveals significant disparities in geographic as well as demographic distributions. These epidemics are evolving and the simple opioid-to-heroin transition story is both supported and challenged by this paper. The opioid pill, heroin and fentanyl crises are intertwined yet increasingly have drivers and outcomes that support examining them as distinct. Addressing these complex and interrelated epidemics will require innovative public health research and interventions which need to consider local and regional contexts.