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Genital mycoplasmas are sexually transmitted Mollicutes with a high prevalence of urogenital tract colonization among females of reproductive age. Current guidelines recommend against routine screening for these organisms, since their role in the pathogenesis of pelvic inflammatory disease and tubo-ovarian abscesses (TOAs) remains unclear. However, genital mycoplasmas harbor pathogenic potential in immunocompromised hosts, especially patients with hypogammaglobulinemia. It is important to identify such infections early, given their potential for invasive spread and the availability of easily accessible treatments. We present a young adult female with multiple sclerosis and iatrogenic hypogammaglobulinemia, with refractory, bilateral pelvic inflammatory disease and TOAs due to Ureaplasma urealyticum, identified as a single pathogen via three distinct molecular tests. To our knowledge, this is the second case of TOAs caused by U. urealyticum in the literature, and the first diagnosed by pathogen cell-free DNA metagenomic next-generation sequencing in plasma.