Background: Metastases to the brain represent a feared complication and contribute to the morbidity and mortality of breast cancer. Despite improvements in therapy, prognostic factors for development of metastases are lacking. KISS1 is a metastasis suppressor that demonstrates inhibition of metastases formation in several types of cancer. The purpose of this study was to determine the importance of KISS1 expression in breast cancer progression and the development of intracerebral lesions. Methods: In this study, we performed a comparative analysis of 47 brain metastases and 165 primary breast cancer specimens by using the antihuman KISS1 antibody. To compare KISS1 expression between different groups, we used a 3-tier score and the automated score computer software (ACIS) evaluation. To reveal association between mRNA and protein expression, we used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. Significance of immunohistochemistry stainings was correlated with clinicopathological data. Results: We identified that KISS1 expression is significantly higher in primary breast cancer compared with brain metastases (P <.05). The mRNA analysis performed on 33 selected ductal carcinoma brain metastatic lesions and 36 primary ductal carcinomas revealed a statistically significant down-regulation of KISS1 protein in metastatic cases (P =.04). Finally, we observed a significant correlation between expression of KISS1 and metastasis-free survival (P =.04) along with progression of breast cancer and expression of KISS1 in primary breast cancer specimens (P =.044). Conclusions: In conclusion, our study shows that breast cancer expresses KISS1. Cytoplasmic expression of KISS1 may be used as a prognostic marker for increased risk of breast cancer progression. © 2011 American Cancer Society.