Objective.Paget’s disease of bone (PDB) is a focal disorder of skeletal remodeling that can lead to bone pain, deformity, and fractures, but it can often be asymptomatic for a long time. This study investigated which factors may distinguish patients with clinical manifestations from asymptomatic patients.Methods.The study group consisted of 224 patients with PDB referred to our Bone Disease Unit. For all patients, data were collected about clinical and demographic variables and diagnostic procedures. Logistic regression analyses were used to assess the role of recorded variables on the odds of being diagnosed clinically rather than by chance.Results.Among the 124 patients with clinical manifestations leading to the diagnosis (55.4%), 36 subjects complained of bone pain, 32 articular pain, 42 back pain, 2 headache; 9 had fractures in Paget bone, and 3 had bone deformity. In 100 patients (44.6%) PDB was diagnosed by chance. At the multivariate analysis, only the number of bones involved (OR for 1 site increment = 1.18, 95% CI: 1.007–1.402; p = 0.04) acted as an independent predictor for a clinical diagnosis. Some skeletal localizations were associated with a clinical diagnosis: the involvement of lumbar spine (OR = 2.085, 95% CI: 1.024–4.224; p = 0.043) was more likely in symptomatic patients; pelvis and tibia showed a borderline statistical significance. The skull was predictive for asymptomatic PDB.Conclusion.A systematic laboratory screening including serum alkaline phosphatase of an older subject complaining of bone pain, articular pain, or back pain is the sole strategy to improve the diagnostic sensitivity for PDB.