Background: The COVID-19 pandemic led to mass vaccination across the globe and resulted in several unintended consequences, one of which being reactive lymphadenopathy mimicking malignancy. A large study reported hypermetabolic lymphadenopathy (HLN) in over 45% of patients after receiving at least one dose of COVID-19 vaccine. A study on breast cancer patients noted a near-400% increase in lymphadenopathy on MRI and ultrasonography over the two years prior to mass vaccination. These findings present a dilemma in patients with treated malignancy while under surveillance. As vaccination became more commonplace, a case series reported on patients with PET-detected lymphadenopathy, with biopsies confirming VRLN. These investigations contributed to general recommendations on the importance of clinical context in patient care after COVID-19 vaccination. We present a unique study that evaluates patients with treated solid and hematological malignancies that presented with HLN after COVID-19 vaccination which emphasizes the importance of clinical acumen in the management of oncological patients in the pandemic era. Methods: We identified 6 patients aged 39-95 with prior malignancy. 5 were diagnosed with metastatic melanoma, and one had a diagnosis of high-grade B-cell lymphoma. Patients were managed with chemotherapy, immunotherapy, surgery, radiotherapy, or a combination of modalities, and were in complete radiological remission. All patients received at least two doses of a COVID-19 vaccine, with one dose at least three weeks prior to a routine surveillance PET-CT. Each patient exhibited HLN. Results: Of six patients, three underwent biopsy. There was no evidence of malignancy in any biopsy, and VRLN was confirmed. The remaining patients were followed with surveillance, and all had resolution of HLN without intervention. Time between COVID-19 vaccination and PET evidence of HLN ranged from 19 to 232 days. Time between first positive and first resolved PET ranged from 92 to 463 days. All patients were alive at the time of abstract submission. Conclusions: Our study emphasizes the importance of a focused history when suspecting recurrent malignancy, especially after sustained remission in our vulnerable populations. Acknowledging that COVID-19 vaccination can lead to HLN is becoming more common, and we show that this can occur, persist, and resolve even months after vaccination. While high suspicion for recurrence should be maintained, all efforts should be taken to protect patients and prevent unnecessary procedures. Records of recent vaccinations should be available and reviewed prior to radiological studies and clinical decisions, which can reduce avoidable interventions and harm. Surveillance of our patients proved to be an appropriate approach, and our study shows that similar patient presentations can have different paths of care depending on the awareness of treating physicians.