Background: Levetiracetam (LEV) is a second-generation antiepileptic drug extensively used in therapeutics. The aim of this study was to evaluate the influence that sex, age, and weight exert on LEV pharmacokinetics in clinical practice. Methods: We conducted a 6-year retrospective observational study. Patients were classified in subgroups according to sex, weight (normal range, overweight, and obese), and age (young adult: 16-30 years old, middle-aged adult: 31-50 years old, advanced adult: 51-64 years old, and elderly adult: >= 65 years old). We compared LEV apparent oral clearance (LEV CL/F) between the subgroups. Results: A total of 238 LEV basal serum concentrations (LEV C-0) corresponding to 156 patients were identified. Significant differences were observed in LEV CL/F between males and females when LEV CL/F was expressed as L/h [mean (SD): 4.79 (1.84) L/h in males versus 4.13 (1.64) L/h in females; P < 0.001]. These differences were not significant when LEV CL/F was normalized by weight [mean (SD): 60.64 (24.90) mL/h/kg in males versus 64.10 (28.87) mL/h/kg in females; n. s.]. Weight in females was 17% lower compared with males. A progressive reduction in LEV CL/F was observed with increasing age, in a proportion that was similar to the decline in renal function. The elderly patients presented 30% lower LEV CL/F (mL/h/kg) and 43% lower creatinine clearance (CCr) in comparison with adults. No statistically significant differences were observed in LEV CL/F calculated in L/h between weight subgroups. However, when LEV CL/F was expressed in mL/h/kg, a progressive reduction was observed [normal weight: 72.21 (28.97); overweight: 57.84 (25.38); obese: 49.45 (14.50); P < 0.001]. A significant and positive correlation between CCr and LEV CL/F was observed, confirming the important role of the renal function in LEV CL/F. The CCr increased in each sex group when weight increased; however, LEV CL/F (L/h) remained constant. Conclusions: Sex, age, and weight affect LEV pharmacokinetics, having an impact on the individual dosage regimen needed to achieve the therapeutic objective. Sex is a conditioning factor of LEV CL/F, although its influence is principally due to the weight. LEV CL/F decreases with advancing age, proportionally to the decline in renal function. It is confirmed that LEV dosage per body weight is not required, and prescribing higher doses of LEV in obese patients is not justified. These data suggest that routine LEV therapeutic drug monitoring in the elderly patients, patients with renal dysfunction, and obese patients is indicated.