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We evaluated and compared the 3-year retention rates of levetiracetam (LEV), topiramate (TPM), and oxcarbazepine (OXC) in patients with epilepsy in routine clinical practice.We retrospectively reviewed medical records of patients with epilepsy who were newly prescribed LEV, TPM, or OXC from 2006 to 2010. The retention rates were estimated by the Kaplan-Meier analysis, and independent risk factors for drug discontinuation were analyzed by the Cox regression method.A total of 588 patients were included: LEV (n = 345), TPM (n = 190), and OXC (n = 53). Among them, 82% had focal epilepsy, whereas 14.8% had generalized epilepsy. The 3-year retention rates for LEV, TPM, and OXC, were 81.2%, 78.3%, and 54.7%, respectively. Levetiracetam and TPM had equivalent retention rates, whereas patients remained on OXC for a significantly shorter amount of time (P < 0.001). A lower retention rate for OXC was also evident in the subgroup analysis of focal epilepsy (P < 0.001). In generalized epilepsy, LEV and TPM revealed comparable retention rates (P = 0.255). The seizure-freedom rate did not differ among groups, whereas the rate of adverse effects leading to drug withdrawal of OXC (87.5%) was higher than that of LEV (34.4%, P < 0.001) and TPM (52.5%, P = 0.012).The current study suggested that LEV and TPM had comparable retention profiles in the long-term treatment for both focal and generalized epilepsy. Meanwhile, OXC therapy seemed to be relatively less useful because of its poor tolerability.