Seasonal variation in immunity has been found in healthy individuals and in association with some diseases. It is still unknown whether seasonal variation affects the clinical course of chronic hepatitis B. Our aim in this study was to explore the effect of seasonal variation on the clinical course of chronic hepatitis B. The flare and remission time of chronic hepatitis B were observed in patients with hepatitis B virus (HBV) infection. All patients enrolled were followed up at least every 3 months for a mean follow-up time of 24.0 (range, 12-60) months. Seasonal decomposition was employed to analyze the relationship between seasonal variation and flares, remission, and hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B patients during follow-up. A total of 2238 patients were observed in our study. Flare and HBeAg seroconversion were seldom seen in 1076 patients (48.08%) with alanine aminotransferase (ALT) levels of less than 2.0 x upper limit of normal (ULN) during follow-up (mean, 36 months). The remaining 1162 patients (51.92%) (766, HBeAg positive; 387 anti-HBeAg positive; 9 negative for both HBeAg and anti-HBeAg) with ALT levels >or=2.0 x ULN were followed longitudinally for 12 months to judge flare, remission, and HBeAg seroconversion. Flare, remission, and HBeAg seroconversion in patients with ALT levels >or=2.0 x ULN showed clear seasonal patterns (P < 0.001), with high peaks during spring, summer, and summer, respectively. An autocorrelation correlogram showed that flares, remission, and HBeAg seroconversion occurred with distinct periodicity in winter, spring, summer, and autumn. Seasonal variation might affect the clinical course of chronic hepatitis B. The role of seasonal triggering factors should be further investigated.