There is concern that influenza vaccine effectiveness (VE) may be attenuated by passage in eggs during manufacture. We compared quadrivalent cell-culture vaccine with egg-based vaccines, most of which were trivalent, against influenza A and B during 2017-2018 when A(H3N2) and B/Yamagata (present only in quadrivalent vaccines) predominated. We retrospectively examined risk of PCR-confirmed influenza A and B in members of Kaiser Permanente Northern California aged 4-64 years. We estimated the relative VE (rVE) of cell-culture vaccine versus egg-based vaccines, and the absolute VE (aVE) of each vaccine comparing vaccinated to unvaccinated individuals. Analyses used Cox regression with a calendar timeline, stratified by birth year, and adjusted for demographics, co-morbidities and utilization. One-third (1,016,965/3,053,248) of the population was vaccinated; 932,545 (91.7% of vaccinees) received egg-based and 84,420 (8.3%) received cell-culture vaccines. The rVE against influenza A was 8.0% (95% CI: -10, 23); aVE was 31.7% (CI: 18.7, 42.6) for cell-culture and 20.1% (CI: 14.5, 25.4) for egg-based vaccines. The rVE against influenza B was 39.6% (CI: 27.9, 49.3); aVE was 40.9% (CI: 30, 50.1) for cell-culture and 9.7% (CI 3.5, 15.6) for egg-based trivalent vaccines. Inclusion of the B/Yamagata lineage in the quadrivalent cell-based vaccine provided better protection against influenza B but vaccine effectiveness against influenza A was low for both the cell-culture vaccine and the egg-based vaccines. Improving influenza vaccines requires ongoing comparative vaccine effectiveness monitoring.