BackgroundInitial D-dimer level is a well-known prognostic parameter in patients with acute ischemic stroke (AIS). However, there have been no studies on the clinical significance of follow-up D-dimer levels. In this study, we evaluated the association between initial and follow-up D-dimer levels and early neurological deterioration (END) in patients with AIS.MethodsWe included consecutive patients with AIS who had a positive initial D-dimer test (> 0.55 mg/L) between March 2021 and November 2022. The follow-up D-dimer test was performed on the 7th day after hospitalization and on the day of discharge if discharged earlier. END was defined as an increase of ≥ 2 in the total NIHSS score, or ≥ 1 in the motor NIHSS score within the first 7 days of admission. As medical conditions closely associated with the initial and follow-up D-dimer levels in AIS patients, we also evaluated the history of cancer, active cancer, and venous thromboembolism (VTE) that occurred during hospitalization together.ResultsA total of 246 patients with AIS were evaluated (median age: 87 years, male: 56.5%). In multivariable logistic regression analysis, the initial D-dimer level was closely associated with END after adjusting for confounders (adjusted odds ratio [aOR]: 1.48, 95% CI: 1.06–2.05). The follow-up D-dimer level also showed a close correlation with END (aOR: 1.60, 95% CI: 1.16–2.20). Regarding the analysis of the association between D-dimer levels and underlying cancer or VTE, the initial D-dimer level showed a statistically significant positive relationship only with active cancer (P= 0.024). On the other hand, the follow-up D-dimer level was found to be statistically significantly associated with a history of cancer (P= 0.024), active cancer (P= 0.001), and VTE (P= 0.001).ConclusionsInitial and follow-up D-dimer levels were associated with END in AIS patients. Particularly, the follow-up D-dimer level showed a clear correlation not only with END but also with the underlying cancer or the occurrence of VTE during the acute period.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12959-023-00496-1.