Trivalent seasonal influenza vaccine effectiveness during the 2015 season in South Africa was assessed using a test‐negative case control study design. Influenza A(H1N1)pdm09 was the dominant circulating strain. Overall influenza vaccine coverage was 3.2% (29/899). The vaccine effectiveness estimate, against any influenza virus infection, adjusted for age, underlying conditions and timing within season was 46.2% (95% CI: −23.5 to 76.5), and 53.6% (95% CI: −62.6 to 80.3) against influenza A(H1N1)pdm09.