Long coronavirus disease (COVID) is defined as an infection-associated chronic condition that occurs after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and is present for at least 3 months as a continuous, relapsing, and remitting, or progressive disease state. While COVID-19 vaccines have been credited by public health officials with preventing COVID-associated morbidity and mortality, a portion of the population reports post-vaccination syndrome, often concerning long COVID. To investigate the association between post-vaccination syndrome and long COVID, we performed an observational cohort study at our outpatient clinical practice, evaluating SARS-CoV-2 semi-quantitative spike Ab in 100 consecutive patients (47% female and 53% male) with symptoms of long COVID. A total of 81 participants (46.9% female and 53.1% male) with post-vaccination syndrome and 19 unvaccinated participants (47.4% female and 52.6% male) with symptoms of long COVID were evaluated. SARS-CoV-2 Semi-Quant Spike Ab in the vaccinated cohort showed an average result of 11356.86 U/mL, whereas SARS-CoV-2 Semi-Quant Spike Ab in the unvaccinated cohort showed an average result of 1631.94 U/mL. The findings reveal potential immune differences in both individuals with long COVID and those with post-vaccination syndrome that merit further investigation to better understand these conditions and inform future research into diagnostic and therapeutic approaches.