Cytokines such as interleukin-1 (IL-1) play a major role in the reparative and inflammatory-like processes that occur in human endometrium during every menstrual cycle, but they also seem to be implicated in critical reproductive events such as ovulation and implantation. Interleukin-1 is tightly regulated in the body by a complex network of control systems. In the present study, we examined the expression of IL-1RII, a natural specific inhibitor of IL-1, in the human endometrium and found an interesting distribution and temporal pattern of expression throughout the menstrual cycle. Immunoreactive IL-1RII was found in stromal as well as epithelial cells, but it was predominant within the lumen of the glands and the apical side of surface epithelium. In situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) analyses showed higher levels of mRNA in epithelial than in stromal cells. The IL-1RII cellular and luminal secretion followed a regulated cycle phase-dependent pattern of expression. Although elevated in the late proliferative/early secretory phase of the menstrual cycle, IL-1RII luminal secretion significantly decreased in the midsecretory phase, reaching its lowest levels at Day 21, before augmenting markedly again during the late secretory phase. This pattern of expression was less obvious at the level of cellular staining, as examined by immunohistochemistry, but it was corroborated by Western blot analysis of IL-1RII protein and semiquantitative RT-PCR of IL-1RII mRNA in the whole endometrial tissue and separated glandular epithelial cells. The reduced expression of IL-1RII within the implantation window suggests the existence of accurate regulatory mechanisms that, by down-regulating IL-1RII expression, alleviate IL-1 inhibition during this crucial period and facilitate IL-1 proimplantation actions. The elevated expression of IL-1RII observed during the late secretory phase suggests an involvement of IL-1RII in control of the proinflammatory state that takes place in the endometrium during the premenstrual and menstrual periods.