The purpose of this study was to determine the effects of smoking history and age on the efficacy and safety of temafloxacin versus ciprofloxacin or amoxicillin in patients with lower respiratory tract infections (LRTIs). Data were pooled from six clinical trials designed to evaluate the efficacy and safety of temafloxacin in bacterial infections of the lower respiratory tract. Patients were selected for this analysis based on smoking history (n = 256) and age (greater than or equal to 65 years of age [n = 328]). Results in the smoker and elderly subgroups were compared between treatment groups and with those in nonsmoker and nonelderly subgroups. Temafloxacin 300 mg or 600 mg b.i.d., ciprofloxacin 500 mg or 750 mg b.i.d., or amoxicillin 500 mg t.i.d. was administered orally for 7-14 days. Patients were assessed at enrollment, on study days 3-7, 24-72 hours post-treatment, and at 5-9 days post-treatment. Temafloxacin and the reference drugs demonstrated comparable clinical efficacy for treatment of LRTI in smokers (93.7% and 92.5%, respectively) and the elderly (94.6% and 89.3%, respectively). However, eradication of baseline pathogens in individual patients was significantly more common after temafloxacin therapy than that following treatment with the reference drugs in both smokers (99.2% versus 91.2%, p = 0.006) and elderly patients (97.5% versus 91.5%, p = 0.028). Overall, eradication rates for pretreatment pathogens were also significantly higher in smokers (99.3% versus 91.8%, p = 0.006) and in the elderly (97.8% versus 92.3%, p = 0.027). Neither age nor smoking status had a consistent effect on the rate of premature discontinuation of study drugs. Adverse events occurred at a similar rate between treatment groups in the elderly and in the smokers. Temafloxacin appears to be a promising alternative to therapy with either ciprofloxacin or amoxicillin in the treatment of respiratory infections in high-risk patients, smokers, and the elderly.