<p>Exosome markers, CD63 and CD81, belong to the tetraspanin family and are expressed in solid tumors. It has been reported that these tetraspanin family members are prognostic factors in some cancers. However, the expression of CD63 and CD81 in pathological breast cancer specimens has not been reported. It has been reported that CD63 promotes the proliferation of breast cancer cells in vitro through yes-associated protein (YAP). Therefore, in this study, the expression of tetraspanin family members, particularly CD63, CD81, and YAP were investigated in breast cancer tissue, by immunohistochemistry, to clarify the relationship between clinicopathological factors and prognosis. The number of CD63 and YAP double-positive breast cancer cells was significantly higher in patients with pathological T factor (pT) status (<i>p</i> = 0.030) and tended to be higher in patients with pathological N factor (pN) status (<i>p</i> = 0.054). Furthermore, the number of CD81 and YAP double-positive breast cancer cells was significantly higher in patients with histological grade (<i>p</i> = 0.015), pT status (<i>p</i> = 0.001), and Ki67 expression (<i>p</i> = 0.049), and tended to be higher in patients with pN status (<i>p</i> = 0.062) and TNM stage (<i>p</i> = 0.052). In addition, CD63 and YAP double-positive breast cancers and CD81 and YAP double-positive breast cancers were associated with shorter disease-free and breast cancer-specific survival, respectively. In conclusion, CD63 and YAP, and CD81 and YAP may serve as potential prognostic biomarkers in patients with breast cancer.</p>