The triggering receptor expressed on myeloid cells (TREM-1) and the myeloid DAP12-associating lectin (MDL-1) are two recently identified receptors which associate non-covalently with DAP12 to form receptor complexes involved in monocytic activation and inflammatory response. In this study, we investigated whether the expression of TREM-1, MDL-1, and DAP12 correlated with myelomonocytic differentiation. Northern and RT-PCR revealed a strong expression of TREM-1, MDL-1, and DAP12 in peripheral blood-derived CD14(+) mature monocytes in contrast to undifferentiated bone marrow CD34(+) stem cells, and in the differentiated versus undifferentiated U937 cells. TREM-1 and MDL-1 RNA expression was also more elevated in adult than fetal tissues and in normal than malignant cells. These findings suggest that the TREM-1/DAP12 and MDL-1/DAP12 signaling pathways are features of mature differentiated myelomonocytic cells. In addition, expression of an alternative mRNA TREM-1 splice variant (TREM-1sv) was detected that might translate into a soluble receptor with potential as a regulator of myeloid activation.