In epilepsy, there is a tendency towards recurrent unprovoked seizures. Seizures result due to the excessive electrical misfiring in the brain between neurons and disturbance in neurotransmitter release. Several gene products affect the behavior of these neurons by regulating neurotransmission via several mechanisms. One such gene, Synapsin-2 (SYN2), involved in synaptogenesis is also reported to regulate the neurotransmitter release. We hypothesized that SYN2 gene and its polymorphisms could affect the process of epileptogenesis and therapeutic response in humans. In this hospital-based study, we enrolled 372 patients with epilepsy and 199 control subjects. We selected rs3773364 A>G polymorphism in SYN2 gene and analyzed its distribution in north Indian patients with epilepsy and control subjects. Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. According to the results obtained, SYN2 “AG” genotype frequency was significantly higher in patients with epilepsy versus control subjects in north Indian population (P = 0.02, OR = 1.55, 95% CI = 1.06–2.26). After subclassification, we observed higher frequency of AG genotype in idiopathic patients as compared to control subjects (P = 0.01, OR = 1.67, 95% CI = 1.08–2.56). There were no significant differences in genotypic (AG: OR = 0.80, P = 0.377; GG: P = 0.628, OR = 1.17) or allelic (P = 0.86, OR = 1.03) frequency distributions in patients with multiple drug resistance versus patients with drug-responsive epilepsy. Results from our study indicate the involvement of SYN2 gene polymorphism in conferring risk to epilepsy; however, the genetic variant does not seem to modulate drug-response in epilepsy pharmacotherapy. Synapse 64:403–408, 2010. © 2009 Wiley-Liss, Inc.