The tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor (TRAIL-R) suppresses inflammation and could therefore affect the course of Chlamydia infections and their long-term sequelae. Wild-type (WT) and TRAIL-R-/- C57BL/6 mice were inoculated vaginally with Chlamydia muridarum; the course of the infection was followed with vaginal cultures and the presence of hydrosalpinx determined. To evaluate the role of TRAIL-R following a secondary infection, the mice were vaginally reinfected. WT and TRAIL-R-/- male mice were also infected and reinfected in the respiratory tract, and the course of the diseases and the infections were followed. Following the primary and secondary vaginal infection, no significant differences in vaginal shedding or hydrosalpinx formation were observed between the WT and TRAIL-R-/- mice. The WT and TRAIL-R-/- mice mounted antibody responses in serum and vaginal washes that were not significantly different. After the primary and secondary intranasal infections of the male mice, changes in body weight were determined, and no significant differences were observed between the WT and TRAIL-R-/- mice. Ten days after the primary and the secondary infections, the weight of the lungs and number of C. muridarum inclusion forming units (IFU) were determined. The lungs of the WT mice weighed less compared with the TRAIL-R-/- mice following a primary infection but not after a secondary infection. No differences in the number of C. muridarum IFU in the lungs were observed between the two groups of mice. In conclusion, despite playing a role in inflammation cell-signaling pathways in vitro, TRAIL-R does not appear to play a major role in the susceptibility, clinical outcomes, or long-term sequelae of C. muridarum infections in vivo. IMPORTANCE TNF-related apoptosis-inducing ligand receptor (TRAIL-R) is involved in suppressing inflammatory responses. Bacterial pathogens such as Chlamydia spp. elicit inflammatory responses in humans following genital, ocular, and respiratory infections. The inflammatory responses are important to control the spread of Chlamydia. However, in certain instances, these inflammatory responses can produce long-term sequelae, including fibrosis. Fibrosis, or scarring, in the genital tract, eye, and respiratory system results in functional deficiencies, including infertility, blindness, and chronic obstructive lung disease, respectively. The goal of this study was to determine if mice deficient in TRAIL-R infected in the genital and respiratory tracts with Chlamydia spp. suffer more or less severe infections, infertility, or lung diseases than wild-type mice. Our results show no differences between the immune responses, infection severity, and long-term sequelae between TRAIL-R knockout and wild-type animals following a genital or a respiratory infection with Chlamydia.