Talc pleurodesis, a frequently performed procedure for refractory pneumothorax or pleural effusion, induces chronic granulomatous inflammation. It can present years later with pleural thickening and markedly increased uptake on positron emission tomography/computed tomography (PET/CT), mimicking the presentation of malignancies. We present the case of a 63-year-old female with positive 18 F-fluorodeoxyglucose PET/CT 20 years after talc pleurodesis. Malignancy such as mesothelioma could not initially be ruled out. CT-guided biopsy confirmed an extensive foreign-body giant-cell reaction consistent with talc-related inflammatory change. This case highlights the need for the consideration of talcoma in the differential diagnosis of patients who undergo talc pleurodesis, and is unique in the significant timespan of 20 years between pleurodesis and positive imaging findings.