Deoxycytidine kinase (dCK) is a critical enzyme involved in intracellular phosphorylation of lamivudine (LAM) to its active triphosphates. We conducted this study to determine dCK polymorphisms in Koreans and to evaluate whether the discovered single nucleotide polymorphisms (SNPs) were associated with treatment outcomes in chronic hepatitis B (CHB) patients treated with LAM. The full-length dCK gene was sequenced from 24 healthy volunteers and 24 patients with CHB. One hundred twenty-seven patients with CHB who were followed-up for at least 24 months after LAM treatment were enrolled. Virological response as determined by undetectable HBV DNA was defined as a good drug response. Primary non-response at 6 months and virological breakthrough within 12 months were defined as a poor drug response. Six novel dCK SNPs were found (−2052C/A, IVS3 − 46G/del, IVS4 + 40G/T, IVS5 + 39T/C, IVS5 − 72A/T, and 966–975T10/T11). In particular, two promoter SNPs, namely −360C/G and −201C/T, were in full linkage disequilibrium. These two SNPs had a higher allele frequency than previously reported in Caucasian, Japanese, and Chinese (26% vs. 2%, 13.1%, and 15.6%, respectively). There was no significant difference between treatment response groups in terms of the distributions of SNP genotypes or allele frequencies. However, there was significant difference in the allele frequency of −360G/−201T between HBeAg seroclearance group and HBeAg non-seroclearance group (P = 0.045). In conclusion, six novel dCK SNPs were discovered. Two promoter SNPs, namely −360C/G and −201C/T, were more frequent in Koreans than other populations. In particular, HBeAg-positive patients with the −360G/−201T haplotype may help HBeAg seroclearance in response to LAM therapy. J. Med. Virol. 88:820–827, 2016. © 2015 Wiley Periodicals, Inc.