The effectiveness of the 2012/13 trivalent seasonal influenza vaccine (TIV) was assessed using a test-negative case-control study of patients consulting primary care with influenza-like illness in the United Kingdom. Strain characterisation was undertaken on selected isolates. Vaccine effectiveness (VE) against confirmed influenza A(H3N2), A(H1N1) and B virus infection, adjusted for age, sex, surveillance scheme (i.e. setting) and month of sample collection was 26% (95% confidence interval (CI): -4 to 48), 73% (95% CI: 37 to 89) and 51% (95% CI: 34 to 63) respectively. There was an indication, although not significant, that VE declined by time since vaccination for influenza A(H3N2) (VE 50% within three months, 2% after three months, p=0.25). For influenza A(H3N2) this is the second season of low VE, contributing to the World Health Organization (WHO) recommendation that the 2013/14 influenza vaccine strain composition be changed to an A(H3N2) virus antigenically like cell-propagated prototype 2012/13 vaccine strain (A/Victoria/361/2011). The lower VE seen for type B is consistent with antigenic drift away from the 2012/13 vaccine strain. The majority of influenza B viruses analysed belong to the genetic clade 2 and were antigenically distinguishable from the 2012/13 vaccine virus B/Wisconsin/1/2010 clade 3. These findings supported the change to the WHO recommended influenza B vaccine component for 2013/14.