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Summary Objective The focus of this study was to ascertain the factors associated with 2009 pandemic influenza H1N1 (pH1N1) infection during different phases of the epidemic. Methods In central Taiwan, 306 persons from households with schoolchildren were followed sequentially and serum samples were taken at three sampling time-points starting in the fall of 2008, shortly after influenza vaccination. Participants who seroconverted between two consecutive blood samplings were considered as having serological evidence of infection. A generalized estimation equation (GEE) with a logistic link to account for household correlations was applied to identify factors associated with pH1N1 infections during the pre-epidemic (April–June) and epidemic (September–October) periods. Results The results showed that receiving an inactivated seasonal influenza vaccine (ISIV) and having a hemagglutination inhibition assay (HI) titer of 40 or higher resulted in a significantly lower likelihood of pH1N1 infection during the pre-epidemic period only, for both children and adults (adjusted odds ratio (OR) 0.3, 95% confidence interval (CI) 0.12–0.9). Having a previous infection by pH1N1 with a baseline titer of 20 or higher resulted in a significantly lower likelihood of infection by pH1N1 during the epidemic period (adjusted OR 0.06, 95% CI 0.02–0.16). Conclusions Our results provide the first serological evidence to suggest a protection effect from receiving an ISIV against pH1N1 infection only when the HI titer reaches 40 or higher during the pre-epidemic period. This study gives an important insight into the control and intervention measures required for preventing infections during future influenza epidemics.