Continued monitoring of the seriousness of influenza viruses is a public health priority. We applied time-series regression models to data on cardio-respiratory mortality rates in Hong Kong from 2001 to 2011. We used surveillance data on outpatient consultations for influenza-like illness, and laboratory detections of influenza types/subtypes to construct proxy measures of influenza activity. In the model we allowed the regression coefficients for influenza to drift over time, and adjusted for temperature and humidity. The regression coefficient for influenza A(H3N2) increased significantly in 2005. The regression coefficients for influenza A(H1N1) and B were relatively stable over the period. Our model suggested an increase in seriousness of A(H3N2) in 2005, the year after the appearance of the A/Fujian/411/2002(H3N2)-like virus when the drifted A/California/7/2004(H3N2)-like virus appeared. Ongoing monitoring of mortality and influenza activity could permit identification of future changes in seriousness of influenza virus infections.