Objective: To evaluate the efficacy and safety of oseltamivir treatment in a population at high risk for influenza. Research design and methods: This was a randomized, open-label, controlled trial involving Chinese patients with chronic respiratory diseases (chronic bronchitis, obstructive emphysema, bronchial asthma or bronchiectasis) or chronic cardiac disease. Patients showing symptoms of influenza were randomly assigned to receive oral oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or symptomatic treatment (control group) within 48 h after symptom onset. Main outcome measures: The main outcome measures were duration and severity of illness in influenza-infected patients. Other outcome measures included incidence of complications, antibiotic use, hospitalization and total medical cost. Results: Of the 118 recruited patients, 56 were identified as influenza-infected through laboratory tests (oseltamivir, N = 27; control, N = 29). Relative to symptomatic treatment, oseltamivir significantly reduced the duration of influenza symptoms by 36.8% (p = 0.0479), and the severity by 43.1% (p = 0.0002). In addition, oseltamivir significantly reduced the duration of fever by 45.2% (p = 0.0051), and the time to return to baseline health status by 5 days (p = 0.0011). The incidence of complications (11% vs. 45%, p = 0.0053) and antibiotic use (37% vs. 69%, p = 0.0167) were also significantly lower in the oseltamivir group compared with the control group. The cost of treating influenza and its complications was comparable between the two groups (p = 0.2462). Conclusions: Oseltamivir is effective and well tolerated in high-risk patients with chronic respiratory or cardiac diseases. It can reduce the duration and severity of influenza symptoms and decrease the incidence of secondary complications and antibiotic use, without increasing the total medical cost.