Little is known about differences between individual hepatitis B genotypes and mutation patterns associated with lamivudine resistance. This study analyses the lamivudine-associated mutation pattern in relation to the four major HBV genotypes A–D. The PubMed database was screened for keywords “HBV OR Hepatitis B,” “YMDD,” “genotype,” and “lamivudine”; all identified publications published till June 2009 were analyzed for differences in mutation pattern. To confirm the literature-based findings the databases of two reference laboratories in Tübingen (Germany), and Melbourne (Australia) were analyzed. Twenty-nine studies were identified reporting 827 patients with known hepatitis B genotype who underwent lamivudine treatment and developed resistance mutations. The literature data revealed that genotype A favors the rtM204V mutation unlike the other major genotypes (P < 0.001), which corresponds to a significant difference in the mutation pattern of genotypes endemic in Asian countries and those found in the rest of the world. These significant findings of the literature-review could be reproduced in the analysis of the databases from Tübingen and Melbourne. Furthermore, the rtL180M mutation is significantly connected to the rtM204V mutation in genotypes A, B, and C, respectively. It is concluded that there is proof that HBV genotypes differ in their mutation pattern of lamivudine resistance. Future studies will need to evaluate whether this will translate into genotype-specific differences in resistance emergence on either entecavir or telbivudine as these antivirals differ in their mutation profile, rtM204V for entecavir and rtM204I for telbivudine. J. Med. Virol. 82:1850–1858, 2010. © 2010 Wiley-Liss, Inc.