Abstract Background High-quality evidence confirms that the clinical efficacy of peramivir in severe influenza patients with primary viral pneumonia is lacking. To optimize clinical medication, we evaluate the different efficacy between peramivir and oseltamivir in the treatment of severe influenza A with primary viral pneumonia. Methods A single-center, randomized, controlled trial was conducted during the Chinese influenza season from December 2018 to April 2019 in patients with severe influenza A with primary viral pneumonia. A total of 40 inpatients were enrolled and treated with either intravenous peramivir (300 mg, once daily for 5 days) or oral oseltamivir (75 mg, twice daily for 5 days). Results The duration of influenza virus nucleic acid positivity in the oseltamivir group and the peramivir group was 2.95 days and 2.80 days, respectively. The remission times of clinical symptoms in the oseltamivir group and the peramivir group were 3.90 days and 3.25 days, respectively. In addition, the remission time of cough symptoms in the peramivir group (63.89 hours) was shorter than that in the oseltamivir group (75.53 hours). There was no significant difference between these values (P > .05). The remission time of fever symptoms in the oseltamivir group was 23.67 hours, which was significantly longer than that in the peramivir group (12.32 hours) (P = .034). Conclusions Peramivir is no less effective than oseltamivir in the treatment of severe influenza A with primary viral pneumonia, and patients treated with peramivir had significantly shorter remission times of fever symptoms than those treated with oseltamivir.