The majority of patients with pandemic influenza H1N1 2009 had mild illness, but some, including those with no risk factors for severe disease, may succumb to this infection. Besides viral factors such as the D222/225G substitution of the hemagglutinin, host factors such as IgG2 subclass deficiency recently was reported to be associated with severe disease in a cohort of Australian patients besides other known risk factors, including underlying chronic illness, extremes of age, and pregnancy. We conducted a case-control study of 38 Asian patients with respiratory failure due to severe pandemic influenza and compared the results to those for 36 mild cases. None had selective IgG2 deficiency, but the level of IgG2 subclass was significantly lower in the severe cases (3.55 g/liter versus 4.75 g/liter; P = 0.002), whereas the levels of IgG1, IgG3, and IgG4 were not significantly different from those of the mild cases. Previous studies suggested that some IgHG2 and FcγRIIa genotypes were associated with IgG2 deficiency. The allelic frequency of the IgHG2 genotypes in our severe cases was not correlated with their levels of IgG2, while that of FcγRIIa was not significantly different from that of the general Han Chinese population (P = 0.216). Only the overall cytokine/chemokine profile (P = 0.029) and serum globulin level (P = 0.005) were found to be independently associated with the IgG2 level by multivariate analysis. The lower IgG2 level in our severe group might be related to cytokine dysregulation rather than being a significant risk factor for severe pandemic influenza. The importance of this finding for therapeutic intervention will require further studies of larger cohorts of patients.