Background: The behavioral changes among Japanese, along with the coronavirus disease 2019 (COVID-19) epidemic, may affect the seasonal influenza epidemic in Japan and change the influenza vaccine effectiveness (VE).

Methods: Influenza VE in children was estimated in the first influenza season (2019/20) overlapping with the COVID-19 epidemic by conducting a single-center, test-negative case-control (TNCC) study. Effects of prior influenza infection and vaccination in children were assessed for the 2019–2020 season.

Results: Among 386 children, the adjusted VE was significant for influenza A/H1N1 (45.5%; 95% confidence interval (CI): 2.0–69.7) and influenza B (66.7%; 95% CI: 35.9–82.7). Among patients aged 0–6 years, the adjusted VE was significant for influenza A (total: A/H1N1+A/H3N2) (65.0%; 95% CI: 22.2–84.3), influenza A/H1N1 (64.8%; 95% CI: 16.9–85.1), and influenza B (87.4%; 95% CI: 50.5–96.8). No VE was observed in patients aged 7–15 years. Two vaccine doses tended to decrease the incidences of influenza A (total) and influenza A/H1N1 in patients aged 0–6 years. The adjusted odds ratios (ORs) of influenza B infection in patients, who had influenza during the previous season, were significantly low among all participants (0.29; 95% CI: 0.11–0.78) and patients aged 7–15 years (0.34; 95% CI: 0.12–0.94). The adjusted ORs of influenza infections were not significant in patients vaccinated during the previous season.

Conclusions: TNCC-based estimates of influenza VE were consistent despite the overlapping COVID-19 epidemic.