The origin of the diverse organic compounds present in carbonaceous chondrites (CC) remains uncertain. We aim at investigating the role that hydrothermal alteration may have had on the molecular evolution of organic matter (OM). In particular, within CC matrices, OM is intimately embedded within phyllosilicates down to the nanometer scale, which raises the question of the influence of phyllosilicates on OM transformation during hydrothermal alteration on parent bodies. We conducted hydrothermal experiments at 150°C and alkaline pH, using a well-known molecule present in processed interstellar ice analogues, the hexamethylenetetramine (HMT), in the presence of Al- and Fe-rich smectites. Experimental products were characterized by gas chromatography mass spectrometry, infrared spectroscopy, X-ray diffraction and synchrotron-based X-ray absorption near edge structure spectroscopy. Within 31 days, the HMT+smectites+H2O system leads to (1) the formation of a diverse suite of soluble organic compounds, yet less abundant and less complex than in the absence of smectite, (2) carbon-rich smectite residues (3.8 wt.% and 2.6 wt.% of carbon for the Al- and Fe-rich smectite residues, respectively). In addition, the abundance and molecular composition of the final organic compounds depend on the nature of the phyllosilicate (Al vs. Fe-smectite). Various and complex interaction mechanisms could occur between OM and smectite. Physisorption, chemisorption and intercalation processes have likely entrapped a significant portion of the organic compounds, thereby altering their chemical evolution. The present work demonstrates that the presence and the nature of phyllosilicates influences the reaction pathways of organic compounds during hydrothermal alteration and that the presence of organic compounds may impact the mineral assemblage. This could have had significant importance for the co-evolution of OM and mineral phases in primitive bodies during hydrothermal alteration.