Experimental protocols are being used increasingly to treat breast cancer with >10 positive nodes. An appreciation of the natural history of this disease is crucial for choosing the optimal therapeutic approach. We retrospectively reviewed the records of 141 patients who had breast cancer with >10 positive nodes and received definitive therapy at our institution in the years 1969 through 1991. Because therapy evolved during this period, we compared the results from 1969 through 1981 to those from 1982 through 1991. Ninety-one patients (65%) were ≥50 years of age. Fifty-four (38%) were estrogen receptor (ER) positive, the remainder were ER negative or ER status unknown. Fifty-seven (40%) had 10 to 15 positive nodes, 63 (45%) had 16 to 25, and 21 (15%) had >25. The ratio of positive nodes to total nodes was <50% in 22 patients, 50% to 75% in 49, and >75% in 70. One hundred thirty-four patients (95%) underwent modified or radical mastectomy. Forty (28%) received adjuvant chemotherapy, including 16 (11%) of 58 patients treated prior to 1981. Eleven patients (8%) were treated with adjuvant radiation therapy. The median survival for all patients was 52 months, with an actuarial survival of 29% at 10 years. Patients treated after 1981 had significantly improved survival. They lived a median of 68 months postoperatively, as compared to 41 months among patients treated earlier. This is a high-risk group of patients, yet there is a small subset who can obtain a long survival with standard treatment modalities.