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Background: Declining efficacy of chloroquine for the treatment Plasmodium vivax malaria has been reported in different endemic settings in Ethiopia. This highlights the need to assess alternative options for P. vivax treatment with artemisinin-based combination therapy, such as pyronaridine-artesunate. This treatment regimen has shown high efficacy for uncomplicated malaria in both Africa and Asia. However, limited data are available from Ethiopia. This study was conducted to assess the efficacy and safety of pyronaridine-artesunate for the treatment of uncomplicated P. vivax malaria in Northwest Ethiopia. Methods: A single arm prospective efficacy study was conducted in the Hamusite area, Northwest Ethiopia. Fifty-one febrile adult patients with uncomplicated P. vivax malaria were enrolled between March and July 2021. Patients were treated with pyronaridine-artesunate once daily for three days. Clinical and parasitological parameters were monitored over a 42-day follow-up period using the standard World Health Organization protocol for therapeutic efficacy studies. Results: A total of 4372 febrile patients were screened with 51 patients enrolled and 49 completing the 42-day follow-up period. The PCR-uncorrected adequate clinical and parasitological response (ACPR) was 95.9% (47/49; 95% CI 84.9–99.0) on day 42. Two patients had recurrences [4.0% (2/49); 95% CI 0.7–12.1] on days 35 and 42. The parasite clearance rate was rapid with fast resolution of clinical symptoms; 100% of participants had cleared parasitaemia on day 1 and fever on day 2. All 16 (31.4%) patients with gametocyte carriage on day 0 had cleared by day 1. There were no serious adverse events. Conclusion: In this small study, pyronaridine-artesunate was efficacious and well-tolerated for the treatment of uncomplicated P. vivax malaria. In adults in the study setting, it would be a suitable alternative option for case management. [ABSTRACT FROM AUTHOR]