Neoadjuvant chemotherapy is standard of care for patients with locally advanced breast cancer. Patients who achieve a pathologic complete response have a more favorable outcome than those who do not; however, a standard system for classifying residual disease has not been adopted. Various definitions of complete response exist, some of which allow for minimal residual invasive or in situ carcinoma. The pattern of residual carcinoma restricted to lymphatic spaces without stromal invasion, herein called pure intralymphatic carcinoma, has not been well addressed. Neither has the pattern of minimal residual stromal invasive cancer accompanied by an extensive intralymphatic component, herein called predominantly pure intralymphatic carcinoma. We report the incidence, clinicopathologic features, and clinical significance of pure and predominantly pure intralymphatic carcinoma in a cohort of 146 neoadjuvant-treated breast cancer patients. We also evaluate the use of the immunohistochemical lymphatic marker D2-40 in these tissues exposed to neoadjuvant chemotherapy. Six patients (4%) had residual pure intralymphatic carcinoma. No gross abnormalities were present in the mastectomy specimens except for 1 case that had a discrete mass, corresponding to residual in situ carcinoma. Residual intralymphatic tumor size ranged from 0.2 to 6 cm. All but one had residual positive lymph nodes. Residual predominantly pure intralymphatic carcinoma was found in 5/146 (4%) patients. A discrete gross mass was observed in 3/5 specimens. Whereas residual stromal invasive carcinoma ranged in size from 0.1 to 1.8 cm, the intralymphatic component ranged from 6 to 9.3 cm. All had residual positive lymph nodes. D2-40 adequately marked lymphatic endothelium in all cases tested. Death occurred in 6/11 (55%) versus 17/135 (13%) patients with or without pure/predominantly pure intralymphatic carcinoma, respectively. After controlling for tumor stage, the presence of either of these residual intralymphatic patterns was associated with a 3-fold increase in death (Cox proportional hazards ratio=3.59, 95% confidence interval, 1.29, 9.99, P=0.014). Elevated risk for disease progression was also observed but this was not statistically significant. We conclude that pure/predominantly pure intralymphatic carcinoma is a clinically significant pattern of residual disease. This may be an underrecognized pattern because of the discordance between gross and microscopic findings and because of challenges in diagnosing intralymphatic carcinoma. D2-40 immunostaining is useful in this setting. Current staging criteria should be clarified to define whether extensive intralymphatic tumor should be incorporated in tumor stage assignment.