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Background Adherence to adjuvant endocrine therapy (AET) is low in women with breast cancer. Negative beliefs about the necessity of AET and high concerns are barriers to adherence. Purpose To use the multiphase optimization strategy to optimize the content of an information leaflet intervention, to change AET beliefs. Methods We conducted an online screening experiment using a 25 factorial design to optimize the leaflet. The leaflet had five components, each with two levels: (i) diagrams about AET mechanisms (on/off); (ii) infographics displaying AET benefits (enhanced/basic); (iii) AET side effects (enhanced/basic); (iv) answers to AET concerns (on/off); (v) breast cancer survivor (patient) input: quotes and photographs (on/off). Healthy adult women (n = 1,604), recruited via a market research company, were randomized to 1 of 32 experimental conditions, which determined the levels of components received. Participants completed the Beliefs about Medicines Questionnaire before and after viewing the leaflet. Results There was a significant main effect of patient input on beliefs about medication (β = 0.063, p <.001). There was one significant synergistic two-way interaction between diagrams and benefits (β = 0.047, p =.006), and one antagonistic two-way interaction between diagrams and side effects (β = −0.029, p =.093). There was a synergistic three-way interaction between diagrams, concerns, and patient input (β = 0.029, p =.085), and an antagonistic four-way interaction between diagrams, benefits, side effects, and concerns (β = −0.038, p =.024). In a stepped approach, we screened in four components and screened out the side effects component. Conclusions The optimized leaflet did not contain enhanced AET side effect information. Factorial experiments are efficient and effective for refining the content of information leaflet interventions. [ABSTRACT FROM AUTHOR]