Heat-induced self-association of regioselectively functionalized 3-O-alkyl celluloses bearing both ethyl- and propyl groups dissolved in water was studied by means of differential scanning calorimetry and oscillatory shear rheology. The measured degrees of substitution were close to 1 but the ratio of ethyl (DSEt) to propyl groups (DSPr) was varied. The aggregation process is intimately coupled with phase separation as shown by the appearance of clouding in the same temperature range. Phase separation is arrested by the incipient gelation; whereby "stronger" gels are produced with high amounts of the propyl substituent than "weaker" phase separating samples as the amount of ethyl groups increases and the amount of propyl groups decreases. The correlation between rheology and thermal analysis clearly demonstrates that aggregation leads to formation of a gel network. It was found that as the ethyl moiety is replaced by propyl group the enthalpies of the thermal transitions increase strongly together with an increase of the elastic modulus (G') and the network is also more coherent with a steady decrease in tanδ (G″/G'). Reversibility was observed on cooling with a marked hysteresis for samples containing high levels of propyl groups. Hysteresis on cooling was explained in term of additional consolidation of the structure occurring at temperature much higher than the aggregation temperature, possibly involving backbone-backbone interactions. Quantitative analysis of the DSC data, based on the two-state thermodynamic model described by Armstrong et al. (1995) enabled evaluation of the van't Hoff enthalpy and the aggregation number. On the basis of those thermodynamic parameters, an "intermolecularly bridged clusters" model is proposed for the heat-induced transition of 3-O-ethyl-propyl cellulose ethers. The van't Hoff enthalpy/calorimetric enthalpy ratio ΔHvH/ΔHcal further indicates on the cooperativity of the process. The number of clusters and indeed the number of molecular chains comprising a cluster are both dependent upon the ratio of the two hydrophobic moieties. An increase in the aggregation number (n) (more aggregates coming together) occurs as ethyl is replaced by propyl, consistent with the observation of a "stronger" gel. The effect of the two different moieties on the physico-chemical properties of 3-O-ethyl-propyl cellulose ethers has been explained in term of different size/hydrophobicity of the two moieties and their distribution.