Lymphocytic infiltration of primary cutaneous melanoma has been demonstrated to be of prognostic significance. Tumor infiltrating lymphocytes (TILs) were evaluated on histologic sections of pT4 primary cutaneous melanoma from 293 patients, accrued in protocols 1690 and 1694 of the Eastern Cooperative Oncology Group. Data for the 60-month follow-up were available. Statistical analysis of the pathologic data evaluated the correlation of regional lymph node metastasis and response to interferon therapy, overall survival, and relapse-free survival. In multivariate analysis, there was significant correlation of the presence of TILs and improved survival. The presence of TILs did not affect the survival of patients treated with interferon alfa-2b. Presence of a localized dominant tumor nodule within the primary tumor had an adverse effect on relapse-free survival (P = .044) that was also marginally present for overall survival (P = .112). The presence of TILs has prognostic but not predictive value, and the presence of a dominant nodule in the primary lesion represents a new adverse prognostic factor that should be incorporated in the evaluation of primary melanoma. This study confirmed the importance of tumor ulceration and the number of positive lymph nodes on outcome.