An increase in generic substitution could be a viable approach to reduce global healthcare expenditures. In many countries, however, generic drug use is rather low. This study examines cognitive predictors (knowledge and beliefs) and affective predictors (general affect and sacred values) to explain generic drug acceptance and use. Data for the study come from a random postal survey conducted in Switzerland (N = 668). A detailed knowledge scale about generic drugs was developed. In addition, an experimental choice task was constructed in which respondents chose between branded and generic drugs. Generic drug acceptance as well as drug choices were influenced by knowledge, beliefs, and affect. It was also found that generic substitution is chosen less frequently for a more severe illness. Key insights could be used for developing information material or interventions aimed at increasing the substitution of generic drugs in order to make health care more affordable.