We describe a new Fourier transform infrared (FT-IR) spectroscopy-based diagnostic approach, which may provide for the first time a rapid, reliable, and inexpensive blood test for scrapie and related transmissible spongiform encephalopathies (TSE). Blood serum from 146 terminally ill Syrian hamsters infected with 263K scrapie via different routes of inoculation and from 166 healthy control animals was analyzed by FT-IR spectroscopy and artificial neural networks (ANN). This revealed characteristic molecular alterations in the serum of infected donors. Different ANN models were constructed and challenged with previously unknown samples in test runs in order to establish whether the new method is able to discriminate between normal and infected animals. Optimized ANNs consistently yielded test sensitivities and specificities of 97% and 100%, respectively. The predictive value of a positive (negative) test was 100% (98%). The proposed serum test circumvents substantial drawbacks of conventional TSE diagnostics and can be fully automated.