Despite advances in treatment, up to 30% of patients with early breast cancer (BC) experience distant disease relapse. However, a comprehensive understanding of tumor spread and site-specific recurrence patterns remains lacking. This retrospective case-control study included 103 consecutive patients with metastatic BC admitted to our institution (2000-2013). Cases were matched according to age, tumor biology, and clinicopathological features to 221 patients with non-metastatic BC (control group). The median follow-up period among the 324 eligible patients was 7.3 years. While relatively low values for sensitivity (71%) and specificity (56%) were found for axillary lymph node (ALN) involvement as an indicator of risk and pattern of distant relapse, nodal status remained the most powerful predictor of metastases (OR: 3.294; CL: 1.9-5.5). Rates of dissemination and metastatic efficiency differed according to molecular subtype. HER2-positive subtypes showed a stronger association with systemic spread (OR: 2.127; CL: 1.2-3.8) than other subgroups. Classification as Luminal or Non-Luminal showed an increased risk of lung and distant nodal recurrence, and a decreased risk in bone metastases in the Non-Luminal group (OR: 2.9, 3.345, and 0.2, respectively). Tumors with HER2 overexpression had a significantly high risk for distant relapse (OR: 2.127) compared with HER2-negative tumors and also showed higher central nervous system (CNS) and lung metastatic potential (OR: 5.6 and 2.65, respectively) and low risk of bone disease progression (OR: 0.294). Furthermore, we found significant associations between biological profiles and sites of recurrence. A new process of clinical/diagnostic staging, including molecular subtypes, could better predict the likelihood of distant relapses and their anatomical location. Recognition and appreciation of clinically distinct molecular subtypes may assist in evaluation of the probability of distant relapses and their sites. Our analysis provides new insights into management of metastatic disease behavior, to lead to an optimal disease-tailored approach and appropriate follow-up.