Abstract Background: We hypothesized that patients diagnosed with stage IV breast cancer at presentation may have different disease characteristics than patients who develop relapsed stage IV disease after adjuvant therapy. To examine potential differences, we analyzed a prospectively collected data set for patients diagnosed at the Markey Cancer Center starting from the beginning of 2007 to date. Methods: Out of 1089 patients, we identified 76 patients (7%) who presented with de novo stage IV disease and 40 patients (4%) who experienced systemic disease relapse after initial adjuvant therapy. We compared key variables between the two groups including patient age, tumor size, grade, estrogen receptor (ER) status, progesterone receptor (PgR) status, HER2, and sites of metastatic disease involvement. Statistical significance was determined using the Chi-square test, Fisher's exact test, two-sample t-test, or Wilcoxon's rank sum test as appropriate. Results: Patients with de novo stage IV breast cancer were more likely to be older (median age 58.5 years, Range 28–88) than women with relapsed stage IV breast cancer (median age 53 years, Range 28–77), and this difference was statistically significant (p = 0.039). As compared to the group with relapsed disease, breast cancer presenting with de novo stage IV disease was more likely to be Grade 1/2 (43% vs. 18.4%, p=0.032), ER positive (69.7% vs. 47.5%, p= 0.019), and PgR positive (56.6% vs. 32.5%, p= 0.0136). Interestingly, de novo stage IV breast cancer was more likely to be HER2 positive than in patients with relapsed disease (27.54% vs. 10.26%, p=0.035). When available patient data prior to 2007 was included in the analysis, we observed no significant difference in the frequency of HER2 expression between the de novo and relapsed groups (27.4% vs. 19.4%, p= 0.26). In comparing sites of metastatic disease involvement, the de novo stage IV patient group was more likely to have bone metastasis than the relapsed disease patient group (68.4% vs. 35%, p = 0.0006). There were no significant differences in the frequency of other metastatic sites involved, including brain, liver, and lung. Conclusions: In this breast cancer patient cohort, there was a relatively high percentage of women presenting with stage IV disease, likely reflecting the underserved nature of this patient population. Women with de novo stage IV breast cancer were more likely to be older, have ER/PgR positive disease, and have bone metastasis as the primary site of involvement. These characteristics may reflect delay in initial presentation rather than a biologically more aggressive disease phenotype. The higher relative frequency of HER2 positive cancer in the de novo stage IV patient group is likely related to the impact of adjuvant trastuzumab use on reducing the risk of relapse in HER2 positive breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-08-23.