The Bcl-2 proto-oncogene product blocks apoptosis. We retrospectively studied Bcl-2 expression in 124 primary tumors from patients diagnosed with T1 (2 cm or less) breast carcinoma with (T1N1) or without (T1N0) lymph-node metastasis. Bcl-2 protein was detected by immunohistochemistry on paraffin-embedded tissue sections. Multivariate logistic regression modeling was used to estimate prevalence odds ratios for lymph-node metastasis. Bcl-2 was widely expressed among T1 tumors showing a strong positive relationship with estrogen (ER)- and progesterone (PR)-receptor-positive tumors. However, a significant inverse correlation was seen between Bcl-2 expression and histological grade, Bcl-2 being absent in the majority of T1 undifferentiated tumors (grade-III carcinomas). Furthermore, Bcl-2 was more frequently expressed in T1N1 cases (72.2%) than in T1N0 specimens (45.7%). The odds for lymph-node metastasis in the Bcl-2-positive group was 3.6 times larger than that in the Bcl-2-negative group. The co-expression of PR significantly modified the effect of Bcl-2 on the odds for lymph-node metastasis, suggesting the existence of a synergistic interaction between the 2 parameters. We studied the percentage of dead cells in primary tumors by in situ DNA fragmentation (FDNA), and found an inverse correlation between Bcl-2 expression and FDNA. This supported the hypothesis that Bcl-2 extends cell survival. In conclusion, our study provides evidence that Bcl-2 expression is involved in breast-cancer progression, at least in a subset of well-differentiated and PR-positive tumors.