Aseptic loosening remains the primary cause of failure in total joint arthroplasty. Substance P (SP)-immunoreactive nerve fibers have been detected in the pseudomembrane and pseudocapsular tissues of aseptic loose hip prostheses, suggesting that SP might be involved in the process of aseptic loosening. We isolated fibroblasts from periprosthetic membrane at the time of revision hip arthroplasty performed because of aseptic loosening. Fibroblasts were incubated in the presence of various concentrations of SP, and the levels of interleukin 1beta, and tumor necrosis factor alpha in the media were determined using enzyme-linked immunosorbent assay kit. We found that the levels of interleukin 1beta and tumor necrosis factor alpha increased in a time- and concentration-dependent manner. Our results suggested that SP might be involved in the pathogenesis of aseptic loosening.