Appreciation of Ureaplasma urealyticum as a human pathogen and documentation of antibiotic resistance have heightened interest in susceptibility testing and treatment alternatives. Treatment of neonates poses special problems because of potential drug toxicity, clinical unfamiliarity with the various conditions that may be due to or associated with ureaplasmal infection, and frequent isolation of the organism from mucosal surfaces in the absence of overt illness. Case reports have undeniably demonstrated the ability of U. urealyticum to cause neonatal bacteremia, pneumonia, and meningitis, although the frequency with which such clinically significant infections occur among the greater population of colonized neonates is unknown. The association of U. urealyticum with development of chronic lung disease of prematurity further intensifies the need for knowledge concerning effective antimicrobial treatment. Despite controversy stemming from nonstandardized susceptibility testing, erythromycin is the drug of choice for treating neonatal ureaplasmal infections not involving the central nervous system. The use of erythromycin is supported by its activity in vitro, limited data from clinical experience, and preliminary pharmacokinetic and safety studies. © 1993, by The University of Chicago.