Background <p>Coxsackievirus A6 (CVA6) has emerged as the predominant cause of hand, foot, and mouth disease (HFMD) in China since the introduction of enterovirus A71 (EV-A71) vaccination. A precise definition of the infectious period is critical for effective containment; however, data on the duration and kinetics of CVA6 shedding remain scarce. We therefore aimed to characterize the viral shedding dynamics of CVA6 and to identify the determinants of viral clearance.</p> Methods <p>We conducted a prospective longitudinal study enrolling pediatric inpatients with laboratory-confirmed CVA6 HFMD between June 2022 and August 2023. Serial pharyngeal swabs were collected every other day during hospitalization and weekly after discharge until two consecutive negative tests were obtained. Shedding duration was analyzed using Kaplan–Meier estimates and Cox proportional hazards models. Viral load was quantified by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and its dynamics were modeled using mixed-effects models.</p> Results <p>Among 88 patients, the median duration of viral shedding was 16 days (95% CI: 14–22), with more than 50% remaining PCR-positive beyond current isolation recommendations. Viral load levels were highest in the first week following symptom onset and tended to show a general progressive decline over the subsequent 5 weeks. Agranulocytosis was associated with prolonged shedding (HR = 0.41, 95% CI: 0.21–0.81, <i>p</i> = 0.010), whereas lymphocytosis accelerated clearance (HR = 1.83, 95% CI: 1.03–3.25, <i>p</i> = 0.039). Elevated aspartate aminotransferase (AST) level was independently associated with higher viral load (<i>β</i> = 0.016, SE = 0.006, <i>p</i> = 0.012).</p> Conclusions <p>CVA6 infection is characterized by prolonged viral shedding, which is modulated by host immune and hepatic factors. These findings highlight the need for evidence-based, serotype-specific public health guidelines in the post-EV-A71 vaccine era.</p>