Background: Type 2 diabetes rates in the general population have risen with the growing obesity epidemic. Knowledge of temporal patterns and factors associated with comorbid diabetes among stroke patients may enable health practitioners and policy makers to develop interventions aimed at reducing diabetes rates, which may consequently lead to declines in stroke incidence and improvements in stroke outcomes. Methods: Using the Nationwide Inpatient Sample (NIS), a nationally representative data set of US hospital admissions, we assessed trends in the proportion of acute ischemic stroke (AIS) patients with comorbid diabetes from 1997 to 2006. Independent factors associated with comorbid diabetes were evaluated using multivariable logistic regression. Results: Over the study period, the absolute number of AIS hospitalizations declined by 17% (from 489,766 in 1997 to 408,378 in 2006); however, the absolute number of AIS hospitalizations with comorbid type 2 diabetes rose by 27% [from 97,577 (20%) in 1997 to 124,244 (30%) in 2006, p < 0.001]. The rise in comorbid diabetes over time was more pronounced in patients who were relatively younger, Black or ‘other’ race, on Medicaid, or admitted to hospitals located in the South. Factors independently associated with higher odds of diabetes in AIS patients were Black or ‘other’ versus White race, congestive heart failure, peripheral vascular disease, history of myocardial infarction, renal disease and hypertension. Conclusions: Although hospitalizations for AIS in the US decreased from 1997 to 2006, there was a steep rise in the proportion with comorbid diabetes (from 1 in 5 to almost 1 in 3). Specific patient populations may be potential targets for mitigating this trend.