The photocatalytic degradation of the X-ray contrast agents iohexol and diatrizoate are monitored by in situ Raman spectrometry measurements in aqueous solution with a TiO2 photocatalyst. Spectral features and changes are interpreted with the use of density functional theory calculations. While we observe similar results to those published previously, significant changes seen in the Raman spectrum allow us to better identify the mechanisms without the need for deductive approaches or complicated sample preparation. Diatrizoate spectra are consistent with hydroxyl radical attack leading to the loss of CO2. Iohexol is more difficult to interpret, representing a current challenge to the use of Raman spectrometry for real-time monitoring of photocatalytic degradation experiments. We explore internal standards that can be added to gauge overall degradation rates to some extent. Potential extensions of the work are described, particularly in terms of increased rate of data acquisition and more general application. Copyright © 2013 John Wiley & Sons, Ltd.