BackgroundAlthough intramural metastasis (IM) in esophageal cancer is considered a poor prognostic factor, there are only limited reports detailing its clinicopathologic characteristics and prognostic impact.Patients and MethodsWe retrospectively included patients with esophageal squamous cell carcinoma (ESCC) with esophagectomy at our institution between 2010 and 2016. We compared patients with intramural metastases (IMs) (IM group) versus those without IMs (non-IM group) to clarify the clinical significance of intramural metastasis in ESCC.ResultsA total of 23 (3.9%) out of all 597 patients were identified to have IM. The IMs were located on the cranial side in 13 (56.5%) and caudal side in 10 (43.5%) of the primary tumor, with two multiple cases. The IM group, compared with the non-IM group, was associated with higher percentage of cN-positive (91.3 versus 67.9%,P= 0.02), pN-positive (82.6 versus 55.9%,P= 0.04), and pM(lym)-positive (30.4 versus 12.5%,P= 0.02) cases. Five-year recurrence-free survival (RFS) was significantly worse in the IM group than the non-IM group (14.9 versus 55.0 %,P< 0.001). Multivariable analysis of recurrence-free survival identified pT (HR 1.74, 95% CI 1.36–2.23,P< 0.001), pN (HR 2.11, 95% CI 1.60–2.78,P< 0.001), histological classification (HR 1.68, 95% CI 1.21–2.35,P= 0.002), and pM(LYM) (HR 1.64, 95% CI 1.64–2.95,P< 0.001), along with presence of IM (HR 2.24, 95% CI 1.37–3.64,P< 0.001) to be independent prognostic factors. Lymphatic (65.2 versus 24.9%,P< 0.001) and hepatic (26.1 versus 6.8%,P= 0.005) recurrences were significantly more common in the IM group than in the non-IM group.ConclusionsIM was shown to be associated with dismal survival after surgery. A treatment strategy emphasizing more intensive systemic control should be considered for patients with ESCC with IM.Supplementary InformationThe online version contains supplementary material available at 10.1245/s10434-023-13464-w.