We report a case of septic arthritis caused by Mycoplasma hominis in a patient with systemic lupus erythematosus. The infection started as monarthritis but spread to at least four joints despite apparently suitable therapy with various antimicrobial agents, including doxycycline, clindamycin, and ciprofloxacin; subsequent bacteremia was documented. Control was ultimately achieved with use of the experimental fluoroquinolone temafloxacin in combination with doxycycline administration, arthroscopic drainage of a persistently infected joint, several intravenous infusions of immunoglobulins (which led to increases in levels of antibodies specific to M. hominis), and discontinuation of corticosteroid therapy. Antimicrobial susceptibility testing of various mycoplasmal isolates showed the presence of the tetM gene, disparity between susceptibility to tetracycline and doxycycline, and increasing resistance to most antimicrobial agents used (including to fluoroquinolones before clinical use), although the patient ultimately had a favorable clinical response to treatment with combined modalities.