Typhoid fever remains a major health problem in developing countries. Fluoroquinolones such as ciprofloxacin emerged as the 1st-choice treatment of enteric fever, including typhoid, in the 1990s. Recently, Salmonella typhi strains with resistance to ciprofloxacin have been increasingly reported in several countries, although the fluoroquinolone-resistant clinical strain has not been reported in Indonesia. In the present study, we examined the drug susceptibility and the presence of gyrA mutations in 17 clinical strains of S. typhi isolated from Surabaya, Indonesia, in 2006 (9 strains) and 2008 (8 strains). Although all 9 isolates from 2006 were sensitive to all tested antibiotics and had no mutation in the gyrA gene, all 8 isolates from 2008 were resistant to nalidixic acid and ampicillin and had a gyrA mutation at codon 87. In addition, 3 of 8 strains from 2008 showed multiple drug resistance, including resistance to chloramphenicol, trimethoprim-sulfamethoxazole, and ciprofloxacin. Therefore, newer drugs, such as ceftriaxone, cefixime, and azithromycin, might be effective in this situation. This is the 1st report of the emergence of fluoroquinolone-resistant clinical strains of S. typhi with a gyrA mutation, and it reveals a health risk due to multidrug-resistant strains in Indonesia.