Increasing evidence supports the involvement of periostin in the pathophysiological processes of stroke and atherosclerosis. The aim of this study was to assess circulating periostin levels at different times after large-artery atherosclerotic (LAA) stroke and their association with stroke. Serum periostin levels were measured using enzyme-linked immunosorbent assay on day 1 in 162 patients with LAA stroke and in 108 age- and sex-matched controls, on day 6 after stroke in 134 patients, and during the 4th week after stroke in 46 of the 162 patients. Stroke severity was determined using the National Institutes of Health Stroke Scale (NIHSS), and the stroke volume was measured. Outcome at 3 months was measured using the modified Rankin Scale (mRS). Our results indicated that periostin levels increased significantly on day 6 after stroke, and this increasing trend persisted for at least 4 weeks after the event. In addition, the increase in periostin levels was positively correlated with the NIHSS scores and stroke volume, but not with the mRS scores after adjusting for the NIHSS scores. In conclusion, these findings suggest that the increase in serum periostin levels observed after stroke may be associated with the stroke severity in patients with LAA stroke.