Nasopharyngeal carcinoma (NPC) patients have elevated IgG and IgA antibody titers against the Epstein-Barr viral capsid antigen (VCA) and the diffuse component of the early antigen complex (EA-D) at diagnosis. Several studies have implied that the presence of anti-VCA-IgA can be used as a screening marker for early NPC. To evaluate this further, we undertook a serologic case-control study based on four serum banks which together had specimens from over 240,000 persons. Seven cases of undifferentiated or poorly differentiated NPC were diagnosed in the period after serum collection ranging from 26 months to 154 months. Two controls per case matched on serum bank, age, sex, race, and date of serum collection were selected by a predetermined random process. For anti-VCA-IgG, the geometric mean titer for cases (88.3) was significantly higher than that for controls (75.5, P less than 0.05). The difference was greatest among the Asian patients. No significant differences were found for anti-VCA-IgA, anti-EA-D, and anti-EA-R or anti-EBNA. No time effects were evident when titers were plotted against time of blood collection preceding diagnosis. Our results do not suggest EBV activation in the period preceding NPC diagnosis, nor that detectable IgA antibody against VCA is a marker for early disease.