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To compare subjective comfort and ocular physiology with three multipurpose solutions (MPSs) to that of a peroxide-based system with three different soft contact lens materials.Habitual soft contact lens wearers (n = 236) were enrolled at three sites and completed a washout period with no contact lens solution for ≥4 days. Subjects were randomly assigned to one of three lens types: etafilcon A, galyfilcon A, or senofilcon A. A new lens of the assigned type was worn for 10 to 14 days each while using one of four care solutions, in random order (A—polyaminopropyl biguanide + polyquaternium, B—POLYQUAD + Aldox, C—alexidine + polyquaternium-1, and D—hydrogen peroxide) with a washout period (≥4 days) between each solution. After each care solution, biomicroscopy was performed and subjective comfort was assessed using the Contact Lens User Experience (CLUE) questionnaire and other instruments including comfortable wear time (CWT). Linear mixed models were used for analysis. Comfort and biomicroscopy signs with each MPS were compared to that of the peroxide solution.Subjective CLUE Comfort score across all lens types with each MPS was not significantly different than with the peroxide solution (p = 0.98). There were no differences in CWT between each MPS and the peroxide solution for any lens type (range of differences: −0.8 to 0.8 h; all p ≥ 0.13). Six MPS/material combinations had no clinically meaningful change in corneal staining versus peroxide (<0.5 units); three combinations could increase staining by up to 0.57 units. Staining was Comparable levels of comfort were found between the latest generation of MPSs compared to peroxide disinfection. Three MPS/material combinations tested could result in increased corneal staining of up to 0.57 units versus a peroxide solution. Overall, these data suggest the care systems investigated are generally appropriate for use with the contact lenses tested.