Abstract Background Hyperglycemia and hyperosmolality are associated with poor outcomes among acute ischemic stroke (AIS) patients. Objectives We evaluated the association between hyperglycemia and hyperosmolality, as a combination measure, with poor outcome among AIS patients. Methods We conducted a retrospective study of AIS patients admitted to the study hospital emergency department between January and December, 2014. Hyperglycemia was defined as serum glucose >144 mg/dL, and hyperosmolality was defined as a serum osmolality >295 mOsm/kg. After excluding hypoglycemia and hypoosmolality, the enrolled patients were classified into four subgroups: normoglycemia-normoosmolality (NGNO), hyperglycemia-normoosmolality (HGNO), normoglycemia-hyperosmolality (NGHO), and hyperglycemia-normoosmolality (HGHO). The primary outcome was poor neurologic status at 6 months, which was defined as a modified Rankin scale score (mRS) ≥ 2. Results 607 patients were included. The primary outcome was 336 (55.4%), and it was highest in the HGNO group (69.6%, 103/148), followed by the HGHO group (67.9%, 53/78), the NGHO group (57.3%, 43/75) and the NGNO group (44.7%, 137/306). The multivariable logistic regression analysis revealed that HGNO and HGHO remained significant factors, with primary outcomes (AOR (95% CI) of 2.08 (1.16–3.71) and 2.93 (1.45–5.91), respectively), whereas NGHO was not a significant factor. Cases of extremely high sodium levels were few in the NGHO and HGHO groups, while considerable cases of extremely high glucose level were observed in the HGHO group. Conclusion Hyperglycemia was associated with poor outcome, even after excluding the effect of hyperosmolality. However, hyperosmolality without hyperglycemia was not associated with poor outcome. An additive effect, likely reflecting severe hyperglycemia, was observed.