Measurements of plasma free metanephrines provide a highly sensitive test for the diagnosis of pheochromocytoma/paraganglioma (PPGL). However, false-positive results remain common, posing a diagnostic dilemma for clinicians. The aim of this study was to determine whether chronic illness and commonly prescribed drugs can falsely elevate plasma free metanephrines. This retrospective study included 460 patients without PPGL. Disease exclusion was based on negative imaging or histopathological findings, or negative biochemistry at follow-up. Sex, age, plasma free normetanephrine, metanephrine, and methoxytyramine, the presence or absence of cardiometabolic comorbidities and/or chronic illness (CCI), and all prescribed medications at study inclusion were reported. In four patients under treatment with norepinephrine reuptake blockers (NRBs), metanephrines were measured at baseline and after short-term discontinuation of the drug. Among the 460 patients without PPGL, 88% (407/460) were receiving at least one medication. In this cohort, false-positive elevations of plasma free metanephrines were rare (7%). Multivariable analysis identified NRBs as the only drugs independently associated with increased plasma free normetanephrine levels (P < 0.001), in a dose-dependent manner. Importantly, plasma free methoxytyramine concentrations were independently influenced by NRBs, antipsychotics, and nicotine use (P < 0.001). Paired analyses in a subset of four patients before and after short-term NRB withdrawal showed normalization of plasma free normetanephrine concentrations. Plasma free metanephrines show high diagnostic reliability with minimal interference from CCI or commonly used medications. However, NRBs can increase normetanephrine and methoxytyramine concentrations, particularly at higher doses, and thus, their use requires cautious interpretation of plasma free metanephrine measurements.