Purpose <p>The uEXPLORER is the first total-body, long-axial field-of-view (LAFOV) PET/CT system available for diagnostic use. The present study aims to assess its clinical impact, with a particular focus on management changes resulting from its use in routine diagnostic workflows.</p> Methods <p>From June to December 2024, consecutive patients undergoing [18&#xa0;F]FDG PET/CT for both oncologic and non-oncologic indications were considered for paired acquisitions using short-axial field-of-view (SAFOV) and LAFOV (uEXPLORER) systems. Scans were independently reviewed by three nuclear medicine physicians. Per-patient and per-lesion analyses were performed. Subsequent clinical management decisions were evaluated to determine the impact of LAFOV imaging. Statistical analyses included kappa statistics, Wilcoxon Signed-Rank Test, and Spearman’s correlation coefficient.</p> Results <p>A total of 124 patients (64% female; median age 65.5 years) were enrolled. Inter-reader agreement was substantial for SAFOV scans (Fleiss’ k = 0.787) and almost perfect for LAFOV scans (Fleiss’ k = 0.853). In per-patient analysis, the two scans were concordant in 85% of cases (Cohen’s k = 0.73). Total lesions identified were 274 on SAFOV PET/CT and 323 on LAFOV PET/CT. Compared to SAFOV, LAFOV imaging detected 52 additional findings in 27 patients (<i>p</i> &lt; 0.05). The per-lesion agreement was 76% (<i>p</i> &lt; 0.05). Of the additional lesions identified by LAFOV PET/CT, 42% were confirmed as true positive. LAFOV findings led to changes in clinical management in 15% of patients, including major therapeutic changes in 68% of these cases.</p> Conclusion <p>LAFOV PET/CT significantly improved lesion detection and influenced clinical decision-making. Further prospective studies are required to validate these findings and fully assess LAFOV systems clinical utility.</p> Trial Registration <p>Not applicable.</p>