Background: As schizophrenia patients are typically suspicious of, or are hostile to changes they may be reluctant to accept generic substitution, possibly affecting compliance. This may counteract drug costs savings due to less symptom control and increased hospitalization risk. Although compliance losses following generic substitution have not been quantified so far, one can estimate the possible health-economic consequences. The current study aims to do so by considering the case of risperidone in Germany. Methods: An existing DES model was adapted to compare staying on branded risperidone with generic substitution. Differences include the probability of non-compliance and medication costs. Incremental probability of non-compliance after generic substitution was varied between 2.5% and 10%, while generic medication costs were assumed to be 40% lower. Effect of medication price was assessed as well as the effect of applying compliance losses to all treatment settings. The probability of staying on branded risperidone being cost-effective was calculated for various outcomes of a hypothetical study that would investigate non-compliance following generic substitution of risperidone. Results: If the incremental probability of non-compliance after generic substitution is 2.5%, 5.0%, 7.5% and 10% respectively, incremental effects of staying on branded risperidone are 0.004, 0.007, 0.011 and 0.015 Quality Adjusted Life Years (QALYs). Incremental costs are (sic)757, (sic)343, -(sic)123 and -(sic)554 respectively. Benefits of staying on branded risperidone include improved symptom control and fewer hospitalizations. If generic substitution results in a 5.2% higher probability of non-compliance, the model predicts staying on branded risperidone to be cost-effective (NICE threshold of 30,000 per QALY gained). Compliance losses of more than 6.9% makes branded risperidone the dominant alternative. Results are sensitive to the locations at which compliance loss is applied and the price of generic risperidone. The probability that staying on branded risperidone is cost-effective would increase with larger compliance differences and more patients included in the hypothetical study. Conclusion: The model predicts that it is cost-effective to keep a patient with schizophrenia in Germany on branded risperidone instead of switching him/her to generic risperidone (assuming a 40% reduction in medication costs), if the incremental probability of becoming non-compliant after generic substitution exceeds 5.2%..