Abstract Body: Objective: To investigate associations of butter and plant-based oil intakes with risk of total and cause-specific mortality.

Participants: 221,054 women and men from the Nurses’ Health Study (1990-2018), Nurses’ Health Study II (1991-2018), and Health Professionals Follow-up Study (1990-2018) were included, all of whom were free of cancer, cardiovascular disease (CVD), diabetes, or neurodegenerative disease at baseline.

Exposure: We assessed dietary intake repeatedly using validated semiquantitative food frequency questionnaires every 4 years. Primary exposures included total butter (butter added at the table and from baking and frying) and plant-based oil intake (safflower, soybean, corn, canola, and olive oil).

Main Outcome: We identified deaths through the National Death Index and other sources. A physician classified the cause of death based on all available records. Total mortality was the primary outcome, and mortality due to cancer and CVD were secondary outcomes.

Results: During up to 28 years of follow-up, we documented 41,618 deaths, including 11,380 from cancer and 9,114 from CVD. After adjusting for confounding factors, the highest butter intake was associated with an 18% higher risk of total mortality compared to the lowest intake (HR: 1.18; 95% CI: 1.10-1.25; P_trend <0.001). Conversely, the highest plant-based oil intake was linked to an 18% lower risk of total mortality (HR: 0.82; 95% CI: 0.76-0.89; P_trend <0.001). Higher olive, soybean, and canola oil intakes were also significantly associated with lower total mortality (all P_trend <0.001). For every 10 g/day increase in plant-based oil intake, cancer mortality risk decreased by 11% (HR: 0.89; 95% CI: 0.85-0.94; P_trend <0.001), and CVD mortality risk by 6% (HR: 0.94; 95% CI: 0.89-0.99; P_trend = 0.03). Higher butter intake was associated with increased cancer mortality (HRper10g/day: 1.12; 95% CI: 1.04-1.20; P_trend <0.001), but not with CVD mortality (P_trend =0.61). Replacing 10 g/day of butter with plant-based oils was associated with a 19% reduction in total mortality (HR: 0.81; 95% CI: 0.77-0.85; P_trend <0.001) and a 20% reduction in cancer mortality (HR: 0.80; 95% CI: 0.74-0.88; P_trend <0.001).

Conclusion: A higher intake of butter is associated with higher mortality, while a higher intake of plant-based oil is associated with lower mortality. Substituting butter with plant-based oils may confer substantial benefits for preventing premature deaths.