Recent data conflict on the clinical efficacy of later-generation fluoroquinolones, such as moxifloxacin or levofloxacin, for the treatment of multidrug-resistant tuberculosis (MDR-TB) that is resistant to ofloxacin but susceptible to moxifloxacin. The purpose of the present study was to evaluate whether later-generation fluoroquinolones can improve treatment outcomes in patients with ofloxacin-resistant, moxifloxacin-susceptible MDR-TB. A retrospective cohort study was performed on 208 patients with moxifloxacin-susceptible MDR-TB who were treated between 2006 and 2011. Later-generation fluoroquinolones were used for all patients. Overall, 171 patients (82%) had ofloxacin-susceptible, moxifloxacin-susceptible MDR-TB (ofloxacin-susceptible group), and 37 (18%) had ofloxacin-resistant, moxifloxacin-susceptible MDR-TB (ofloxacin-resistant group). Compared to the ofloxacin-susceptible group, the ofloxacin-resistant group was more likely to have a history of MDR-TB treatment ( P < 0.001) and cavitary lesions on chest radiography ( P < 0.001). In addition, the ofloxacin-resistant group was more likely than the ofloxacin-susceptible group to have resistance to the drugs pyrazinamide ( P = 0.003), streptomycin ( P = 0.015), prothionamide ( P < 0.001), and para-aminosalicylic acid ( P < 0.001). Favorable outcomes were more frequently achieved for the ofloxacin-susceptible group than for the ofloxacin-resistant group (91% [156/171] versus 57% [21/37], respectively [ P < 0.001]). In multivariable regression logistic analysis, the ofloxacin-susceptible group was about 5.36 (95% confidence interval, 1.55 to 18.53) times more likely than the ofloxacin-resistant group ( P < 0.001) to have favorable outcomes. Despite in vitro moxifloxacin susceptibility, the frequency of favorable treatment outcomes for ofloxacin-resistant MDR-TB was significantly lower than that for ofloxacin-susceptible MDR-TB, even when later-generation fluoroquinolones were used, indicating that more-aggressive therapies may be needed for ofloxacin-resistant MDR-TB.