Nasopharyngeal carcinoma (NPC) is a complex disease caused by an interaction of EBV chronic infection, environment and host genes, in a multi-step process of carcinogenesis. However, which genetic factors play an important role in the development of chronic EBV infection and NPC remain elusive. The objective of this study is to identify genetic variations associated with two key clinical stages of NPC development: persistent Epstein-Barr virus (EBV) infection of nasopharyngeal epithelia and progression to NPC. We inspected a NPC-associated region on the short arm of chromosome 4 previously implicated by a genome-wide linkage analysis of familial NPC. We determined genotypes for 319 alleles in 34 microsatellite markers spanning an 18 Mb region in 350 NPC cases, 288 individuals with IgA antibodies to EBV capsid antigen (IgA/VCA+) and 346 controls seronegative for IgA antibodies to EBV capsid antigen (IgA/VCA-). The cases and controls were Han Chinese from Wuzhou city and Cangwu County, Guangxi province where the incidence of NPC is as high as 25-50 per 100,000 individuals. Comparing NPC cases to IgA/VCA+ subjects, we found 9 alleles marginally associated with developing NPC from IgA+ status, 5 for risk (OR=1.51-5.36, P=0.01-0.03) and 4 for restrictive (OR=0.3-0.71, P=0.02-0.045). Comparing IgA/VCA+ subjects and IgA/VCA- controls, and comparing all IgA seropositives with and without NPC to IgA seronegatives revealed 12 significant and 3 highly significant (P<0.01) alleles associated with IgA+ serostatus in the two comparing groups. Alleles D4S3241-136 (P=0.004, OR=1.91, 95% CI=1.2-3.0) and D4S3347-213 (P=0.001, OR=1.6, 95% CI=1.2-2.1) were for risk. Allele D4S174-202 (P=0.001, OR=0.5, 95%CI=0.3-0.7) was restrictive. However, statistical significance was lost for all when corrected for multiple comparisons test. Our study could not affirm the genetic association within this region with NPC as did another pedigree study, but provide an opportunity for further gene discovery in this highly endemic NPC population and suggest that this region warrants further study.