Several solid acidic catalysts have been investigated for the Prins condensation of iso-butyl aldehyde with tert-butyl alcohol in a liquid-phase reaction. The results demonstrate that acidic molecular sieves are effective catalysts for the condensation reaction, and HZSM-5 molecular sieves possessed strong enough acidity and proper channel systems exhibit high catalytic performance. Solvent polarity and solvent-active site interaction would significantly affect the aldehyde conversion and the 2,5-dimethyl-2,4-hexadiene selectivity. The iso-butyl aldehyde to tert-BuOH ratio, catalyst amount, solvent amount, reaction temperature, reaction time, Si/Al ratio of HZSM-5 molecular sieves, catalytic performance of different solid acids, and side-reactions in the system are studied. Up to 78.6% iso-butyl aldehyde conversion is obtained with a 57.8% 2,5-dimethyl-2,4-hexadiene yield over HZSM-5 with Si/Al of 39 after 8 h at 160degreesC, which provides a useful and economical potential industrial application way on a large scale to manufacture 2,5-dimethyl-2,4-hexadiene. (C) 2004 Elsevier B.V. All rights reserved.