Headache is a frequent accompaniment of acute ischaemic stroke. The predisposing factors and underlying mechanisms are currently incompletely defined. We analysed prospectively collected data relevant to headache occurring at ischaemic stroke onset in consecutive patients included in the Henry Ford Hospital Stroke Data Bank. Patients with headache (HA+) and without headache (HA–) were compared for demographic factors, medical history, medications, examination findings, laboratory findings, and stroke localization and subtype. Group comparisons for categorical data were performed with χ2 test, and for continuous variables with two-sample t-tests. Stepwise logistic regression analysis, including all variables with P < 0.25, was used to define the independent predictors of onset headache. Three hundred and seventy-five patients had complete headache and clinical datasets and were included in the analysis (HA+, N = 118; HA–, N = 257). Multivariate analysis revealed that the independent predictors of HA+ were: infarct in the distribution of the posterior circulation [P = 0.0076, odds ratio (OR) 2.15, 95% confidence interval (CI) 1.23, 3.77], absence of history of hypertension (P = 0.0106, OR 0.48, 95% CI 0.27, 0.84), and treatment with warfarin at the time of the index stroke (P = 0.0135, OR 4.89, 95% CI 1.39, 17.21). The occurrence of headache at onset of ischaemic stroke is determined by posterior circulation distribution of the ischaemic event, absence of history of hypertension and treatment with warfarin at the time of the index stroke. These results suggest that preserved elasticity and maintenance of the intracranial vasculature in a relaxed state, in combination with coagulation system derangements, and activation of dense perivascular afferent nerves, play a role in the pathogenesis of onset headache.