Xanthomonas maltophilia is an emerging nosocomial pathogen, possibly selected by a changing antimicrobial usage and patient population. In the present study, we tested the susceptibility of 33 recent clinical case isolates to 12 commonly employed antimicrobials. Trimethoprim-sulfamethoxazole (1:19 ratio) and doxycycline were uniformly the most active agents; ciprofloxacin and fleroxacin were slightly less active and, along with tetracycline and ceftazidime, more variable in their potency. Interestingly, the disk diffusion method routinely overstated the activity of ciprofloxacin (12% very major errors, 58% minor errors). The present in vitro data and the hitherto accumulated clinical experience suggest that in the absence of unequivocal clinical efficacy of ciprofloxacin against this increasingly recognized nosocomial pathogen, the decision to use ciprofloxacin or any other fluoroquinolone against these pathogens should rely preferentially on the dilution susceptibility test method results. In contrast, the present study confirms the excellent predictive value of trimethoprim-sulfamethoxazole, tetracycline, and fleroxacin disks as well as the higher (9% minor errors) inhibitory activity of these drugs. Hence, pending the elaboration of clinical efficacy data of alternative antimicrobial agents against X. maltophilia infections, trimethoprim-sulfamethoxazole remains a sound therapeutic choice.