Ureaplasma urealyticum and Ureaplasma parvum are important causes of septic arthritis in patients with hypogammaglobulinemia. The diagnosis can be challenging, leading to prolonged illness and increased morbidity, and mortality. This is driven by the complex growth media requirements of Ureaplasma species and the difficulty in identifying the organisms on routine culture media. Herein, we present a case of native joint polyarticular septic arthritis and vertebral infection secondary to disseminated U. urealyticum in a patient maintained on rituximab. The diagnosis was established through a positive species-specific U. urealyticum polymerase chain reaction (PCR) after a meticulous workup including synovial fluid biopsy, cultures and broad-range bacterial PCR returned negative. Septic arthritis caused by Ureaplasma species should be considered in the differential diagnosis especially in immunocompromised patients with hypogammaglobulinemia, even if the initial microbiological workup is non-revealing. Delayed diagnosis and treatment are associated with increased morbidity.