Introduction Influenza A(H3N2) clades 3C.2a and 3C.3a co-circulated in Europe in 2018/19. Immunological imprinting by first childhood influenza infection may induce future birth cohort differences in vaccine effectiveness (VE). Aim The I-MOVE multicentre primary care test-negative study assessed 2018/19 influenza A(H3N2) VE by age and genetic subgroups to explore VE by birth cohort. Methods We measured VE against influenza A(H3N2) and (sub)clades. We stratified VE by usual age groups (0\textendash 14, 15\textendash 64, ≥q\,65-years). To assess the imprint-regulated effect of vaccine (I-REV) hypothesis, we further stratified the middle-aged group, notably including 32\textendash 54-year-olds (1964\textendash 86) sharing potential childhood imprinting to serine at haemagglutinin position 159. Results Influenza A(H3N2) VE among all ages was -1% (95% confidence interval (CI): -24 to 18) and 46% (95% CI: 8\textendash 68), -26% (95% CI: -66 to 4) and 20% (95% CI: -20 to 46) among 0\textendash 14, 15\textendash 64 and ≥q\,65-year-olds, respectively. Among 15\textendash 64-year-olds, VE against clades 3C.2a1b and 3C.3a was 15% (95% CI: -34 to 50) and -74% (95% CI: -259 to 16), respectively. VE was -18% (95% CI: -140 to 41), -53% (95% CI: -131 to -2) and -12% (95% CI: -74 to 28) among 15\textendash 31-year-olds (1987\textendash 2003), 32\textendash 54-year-olds (1964\textendash 86) and 55\textendash 64-year-olds (1954\textendash 63), respectively. Discussion The lowest 2018/19 influenza A(H3N2) VE was against clade 3C.3a and among those born 1964\textendash 86, corresponding to the I-REV hypothesis. The low influenza A(H3N2) VE in 15\textendash 64-year-olds and the public health impact of the I-REV hypothesis warrant further study.