21019 Background: Women diagnosed with lymph node positive breast cancer have a greater chance of recurrence and death than women with lymph node negative disease. Tumor markers are becoming increasingly important to understanding breast cancer progression, yet little is known about their relationship with lymph node status. The purpose of this study is to examine whether prognostic and novel cell-cycle tumor markers are associated with lymph node status in black and white women with invasive breast cancer. Methods: This study included 202 lymph node positive and 292 node negative women, ages 20–54 years, diagnosed with invasive breast cancer between 1990 and 1992, and previously enrolled in a population-based study in Atlanta, Georgia. Tumor specimens were centrally reviewed and evaluated for lymphovascular invasion (LVI) and Nottingham tumor grade. Expression of estrogen and progesterone receptors (ER and PR), c-ErbB-2, Ki-67, pRb, p16, p21, p27, p130/Rb2, p53, cyclin E, and cyclin D1 were centrally assayed by immunohistochemistry. Relationships between each tumor marker and lymph node status were assessed by logistic regression, after adjusting for prognostic and socio-demographic factors. Results: Several tumor markers were associated with lymph node status, but differed by tumor size. Among women with smaller tumors (≤2.0 cm), p130 (OR=0.6, 95% CI 0.4–1.0), Bcl-2 (OR=0.4, 95% CI 0.2–0.8), and cyclin D1 (OR=1.7, 95% CI 1.0–2.8) were significant predictors of positive lymph node status. Among women with tumors > 2.0 cm, p53 (OR=0.5, 95% CI 0.3–0.8), and cyclin E (OR=0.4, 95% CI 0.2–0.9), and pRb (OR=1.6, (95% CI 1.0–2.6) were significant predictors. Black women with smaller tumors were 50% more likely to have lymph node metastasis. LVI and high grade remained the strongest predictors of lymph node metastasis in all regression models. Conclusions: Our findings suggest that there may be a different mechanism for lymph node spread in aggressive smaller tumors compared to larger tumors. Identifying markers for aggressive tumors could lead to the benefit of more effective treatment, particularly among black women for whom race may be a surrogate for other markers not accounted for in our study. No significant financial relationships to disclose.