Background: The present work aimed to estimate the economic impact of PTSD following COVID-19 in a population of patients affected by systemic autoimmune disease (SAD) using a cost-of-illness approach and accounting for the perspective of society. Methods: Considering data collected from SAD patients enrolled in a specialized outpatient clinic in the Tuscany region, Italy, generalized linear models and LASSO logistic regression were used to evaluate the impact of PTSD on costs and its relevance as a possible predictor of being a high-cost patient, respectively. Results: Considering 301 SAD patients, 161 (51.2%) of whom were diagnosed with PTSD, the overall costs were EUR 3670 [890; 40,529] per patient/year among patients with PTSD and EUR 2736.7 [283; 21,078] per patient/year among those without PTSD (p-value < 0.001), with differences mainly attributable to significantly greater direct non-healthcare and indirect costs. PTSD was estimated to increase overall costs (β = 0.296 (0.140), p-value = 0.035), direct non-healthcare (β = 1.193 (0.392), p-value = 0.002), and indirect costs (β = 3.741 (1.136), p-value = 0.001). PTSD diagnosis was also significantly associated with the likelihood of being a high-cost patient. Conclusions: Findings from the present study offer a novel perspective on the economic impact of COVID-19 and provide valuable data for policymakers to better understand the demand for healthcare services and associated costs.