Purpose. To evaluate the clinical performance of a silicone hydrogel (Si-Hy) soft contact lens (CL) in combination with three different multipurpose disinfecting solutions (MPDSs). Methods. This was a prospective, randomized, single-masked, crossover, and comparative study in which 31 habitual soft CL wearers were randomly assigned to one of the three MPDSs (Synergi, COMPLETE RevitaLens, and OPTI-FREE PureMoist) for 1 month with a 1-week wash-out period between each exposure. All subjects were successfully refitted with a Si-Hy CL (Biofinity). Subjects were then scheduled for follow-up visits after 1 month of lens wear, being evaluated at 2 and 8 hours after lens insertion. Visual Analogue Scales (VAS) were used to gauge comfort rating. Results. The tarsal conjunctiva showed a significantly different degree of lid redness between the MPDSs at the 2-hour visit (P < 0.05, Kruskal-Wallis test), being lower for COMPLETE RevitaLens compared to the other two MPDSs (Mann-Whitney U test). Furthermore, a significantly different degree of lid roughness at the 8-hour visit was seen (P < 0.05, Kruskal-Wallis test), being higher for Synergi (Mann-Whitney U test). The subjective comfort was similar with the three MPDSs. Conclusion. Tarsal conjunctival response should be also considered in the context of the clinical performance of MPDs at the ocular surface.