Abstract Funding Acknowledgements None. Introduction Post-COVID-19 syndrome (PCS) refers to a wide spectrum of health issues experienced by individuals who have previously had COVID-19, starting three months after acute COVID-19 and enduring for a minimum of two months. Approximately 20% of PCS patients encounter inappropriate sinus tachycardia (IST), defined as the mean 24-hour heart rate greater than 90 bpm. IST is often accompanied by symptoms including palpitations and breathlessness that hinder patients in their daily tasks. Previous research has suggested that dysautonomia, a dysfunction in the autonomic nervous system, might underlie most PCS symptoms. Yet, its role in the development of IST within the context of PCS has not been fully investigated. Purpose This retrospective study examines IST prevalence and cardiovascular symptoms in PCS patients. It also assesses cardiac autonomic function through analysing the time and frequency fluctuations between successive heart rates, termed heart rate variability, to investigate the role of dysautonomia in the development of IST in PCS. Methods Patients who continued to experience PCS symptoms 12 weeks after their initial SARS-CoV-2 infection were referred to a multidisciplinary PCS unit at our hospital. Using our electronic patient record system, we identified 685 eligible patients who underwent 24-hour Holter monitoring between March 2020 and February 2023. After excluding patients with various conditions that could affect heart rate, we performed a comparative sub-analysis on 524 patients, dividing them into two age- and gender-matched groups of IST (n=100) and non-IST (n=424). The ECG data extracted from the 24-hour Holter records of these patients were entered into the KUBIOS software for HRV analysis and assessment of sympathetic and parasympathetic activity which could indicate cardiac dysautonomia. Demographic data was analysed using basic descriptive statistics and a chi-square test between the two groups. The normality of each parameter was tested using the Shapiro-Wilk test. Using Mann-Whitney and unpaired t-tests, we statistically analysed the differences between the IST and non-IST groups on the GraphPad Prism software. Results The LF/HF ratio was significantly higher in the IST group (2.78 ± 1.89) compared to the non-IST group (2.15 ± 1.93, p<0.001). The sympathetic nervous system (SNS) index was significantly higher in the IST group (1.50 ± 0.77 versus -0.13 ±0.70, p<0.001), whilst the parasympathetic nervous system (PNS) index was significantly lower in the IST group (-1.75 ± 0.65 versus -0.16 ± 1.61, p<0.001). Conclusions In PCS patients with IST, cardiac dysautonomia leads to a shift in the cardiac sympathovagal balance towards PNS and subsequently increased SNS activity, with a more pronounced effect on the parasympathetic side. Addressing dysautonomia and promoting parasympathetic activity could thereby improve PCS diagnostic and treatment strategies to restore a balanced autonomic regulation of the heart.