Epilepsy is one of the most prevalent neurological disorders, affecting approximately 1% of the world population. Despite the availability of dozens of antiepileptic drugs (AEDs) in clinical practice, the number of patients who do not respond to treatment and/or exhibit high pharmacokinetic variability remains significant, highlighting the importance of therapeutic drug monitoring (TDM). Plasma and serum are the main biological matrices applied for the TDM of AEDs, but the necessity of a specialized professional has been an obstacle to sample collection in ambulatory. Thus, drug quantification in saliva arises as a promising alternative. Herein, a novel highperformance liquid chromatographic (HPLC) technique with diode-array detection (DAD) was developed and fully validated, in order to simultaneously quantify carbamazepine, carbamazepine-10,11-epoxide, S-licarbazepine, lacosamide and levetiracetam in human saliva. The technique was linear in the following concentration ranges: 0.2-6 mg L-1 for carbamazepine and carbamazepine-10,11-epoxide; 0.3-9 mg L-1 for S- licarbazepine; 1-30 mg L-1 for lacosamide; and 0.8-24 mg L-1 for levetiracetam. The lower limits of the established calibration ranges are below therapeutic margins, attesting a sensitive drug quantification. Accuracy values ranged from -14.76 to 9.35 % and -12.87 and 11.18 % in intra-day and inter-day analysis, respectively. Intra-day values of precision varied between 3.45-10.76% and inter-day values ranged from 3.85 to 13.05 %. This method was subsequently applied to saliva samples of epileptic patients admitted to the Refractory Epilepsy Centre of Centro Hospitalar e Universitário de Coimbra (CHUC EPE, Coimbra). The results of saliva samples were correlated with drug concentrations in plasma from the same patients. Statistically significant correlations were observed (p < 0.05) for carbamazepine (r2 = 0.6887; r = 0.8299), carbamazepine-10,11-epoxide (r2 = 0.8633; r = 0.9291), S-licarbazepine (r2 = 0.5266; r = 0.7257) and levetiracetam (r2 = 0.7103; r = 0.8428). Our data support that this method can be used in TDM of AEDs using human saliva samples, constituting a new approach to establish individual therapeutic ranges and assess patient's adherence to treatment.