Background: The risk of symptomatic infarct swelling has been reported to be higher in patients treated with recombinant tissue plasminogen activator (rt-PA). The aim of this study was to evaluate the timing of symptomatic infarct swelling after rt-PA treatment. Methods: We retrospectively analyzed 14 868 patients with acute ischemic stroke from a stroke registry databank. We recruited patients with massive middle cerebral artery (MCA) infarction and symptomatic infarct swelling and excluded those with parenchymal or symptomatic hemorrhage. Multiple linear regression and multivariate logistic regression analyses were used to estimate the impact of rt-PA on the timing of symptomatic infarct swelling. Results: A total of 23 patients with rt-PA treatment and 117 patients without rt-PA treatment were included. The rt-PA treatment group had a lower rate of coronary artery disease (8.7% vs 32.5%; P =.023), lower severity of baseline National Institutes of Health Stroke Scale score (19 vs 23; P =.014), shorter duration of infarct swelling (27.6 vs 45.4 hours; P <.001), and higher rate of hemicraniectomy surgery (65.2% vs 28.2%; P =.001) than those without rt-PA treatment. After adjusting for variables in multiple linear regression analysis, rt-PA treatment and an elevated C-reactive protein level were associated with early symptomatic infarct swelling (P =.014 and P =.041, respectively). The rt-PA treatment was an independent factor related to early symptomatic infarct swelling within 36 hours (P =.005; odds ratio [OR]: 5.3; confidence interval [CI]: 1.65-17.0) or 48 hours (P =.009; OR: 16.4; CI: 2.00-134). Conclusion: Intravenous rt-PA treatment may hasten the onset of cerebral edema and subsequent cerebral herniation in large MCA territory infarction.