Background <p>Sodium valproate (VPA) is widely recognized as the first-line treatment for patients with epilepsy (PWE). However, current studies lack evidence to determine the best add-on medication following VPA monotherapy failure. Lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), topiramate (TPM), and carbamazepine (CBZ) also exhibit broad-spectrum activity for seizures. This study aims to compare the therapeutic efficacy of different anti-seizure medication combinations in PWE following valproate monotherapy failure.</p> Methods <p>Individuals were categorized into five groups: VPA + LTG, VPA + LEV, VPA + TPM, VPA + OXC and VPA + CBZ. Each group was further subdivided based on seizure type: generalized onset, focal onset, or unknown onset. The effectiveness of these five groups was compared using variance, χ² test and Kaplan–Meier survival analysis.</p> Results <p>A total of 2656 PWEs were included in this study. The ≥ 50% response rates for subjects with generalized epilepsy when combining VPA with LTG, OXC, LEV, TPM, and CBZ were 89.6%, 81.0%, 77.9%, 77.7%, and 75.9%, respectively. The LTG group demonstrated significantly higher efficacy than the LEV, TPM, and CBZ groups (<i>P</i> &lt; 0.05). The ≥ 50% response rate of LTG, OXC, LEV, TPM and CBZ for subjects with focal epilepsy were 86.3%, 88.9%, 79.3%, 75.9% and 74.8%, respectively; with the OXC group being significantly more effective than the LEV, TPM, and CBZ groups (<i>P</i> &lt; 0.05).</p> Conclusions <p>In this real-world study, we assessed the effectiveness of five anti-seizure medications as add-on therapy for PWE who failed sodium valproate monotherapy. Our findings suggest that combining LTG may be more effective for subjects with generalized epilepsy, while combining OXC may be more effective for subjects with focal epilepsy.</p>