The aggregation process of Carbopol 934NF, a Food and Drug Administration approved cross-linked poly(acrylic acid) commonly used in pharmaceutical technology, with nonionic and ionic surfactants in 0.9% NaCl dispersions and artificial lacrimal fluid was analyzed using titration microcalorimetry and rheometry. Titration microcalorimetry experiments indicated that the interaction processes in 0.9% NaCl are thermodynamically similar to those in water, although slightly less intense. In contrast, in artificial lacrimal fluid the carbopol-surfactant interactions were hindered. Carbopol association with Tween 80 (exothermic) or Pluronic F-127 (endothermic) occurs through hydrogen-bonding interactions, which are scarcely debilitated in 0.9% NaCl but strongly impeded in artificial lacrimal fluid. In this medium, the higher pH causes more carboxylic acid groups to become ionized, and the presence of calcium ions blocks them partially. In 0.9% NaCl, there is a shielding effect of the ionic groups of the polymer that promotes the hydrophobic association with sodium dodecyl sulfate and makes the complex formation with benzalkonium chloride more difficult. In both cases, the processes were exothermic. In artificial lacrimal fluid, the interaction with sodium dodecyl sulfate disappears while an endothermic association with benzalkonium chloride takes place. The ion-induced changes in the intensity of the carbopol-surfactant association are reflected in the rheological behavior of the 0.25% acrylic polymer dispersions. The results show that the nature and concentration of ions may have a strong influence on the design and on the physiological behavior of drug delivery systems based on carbopol gels.