Introduction: Monkeypox (mpox) is an emerging infectious disease. Since May 2022, mpox cases have spread beyond endemic regions, including Argentina. The gold standard diagnostic method is nucleic acid amplification testing (NAAT) from skin lesion swabs. However, this approach can be invasive and less effective for detecting asymptomatic or presymptomatic infections, highlighting the need to explore alternative methods such as saliva sampling. Methods: This observational cohort study included 56 patients from an hospital in Buenos Aires, between June and November 2022. Paired samples of saliva and skin swabs were collected from 32 participants and tested using RT-PCR. Results: Of the 32 paired samples, 17 (53.1%) tested positive for mpox. Saliva showed a sensitivity of 88.2% and a specificity of 100% compared to skin swabs. Higher Ct values were observed in saliva than in skin samples (p<0.001). Conclusions: Saliva sampling is a feasible alternative for mpox diagnosis, enabling patient self-collection and improving early detection, particularly in asymptomatic cases. This method could enhance monitoring efforts, especially in challenging epidemiological scenarios.