Purpose: To investigate the ocular subclinical inflammatory response in two soft contact lens materials when used in combination with two different care systems (‘solutions’). Methods: Fifteen established soft contact lens wearers wore each of two lenses: Acuvue® 2 (CH) and Acuvue® Oasys® (SiH) or no lenses in random sequence for one week. Two care systems were used: a peroxide system: Oxysept 1 Step® (P) for the right lens and Opti-Free® Replenish® (MPS) for the left lens. After one week of lens/no lens wear, in vivo confocal microscopy (IVCM) of corneal and conjunctival regions was carried out. Density of presumed dendritic cells (DC) and ‘white spots’ (WS) were quantified. Impression cytology of the bulbar and upper eyelid margin conjunctivae was carried out and samples were analysed for CD45+, CD3+ and CD11c+ cells. Results: The SiH + MPS combination showed a greater inflammatory response compared to SiH + P in seven out of 12 parameters investigated (p < 0.05). The remaining five were not statistically different between the two solutions. The converse was found for the CH lens, with four of the 12 parameters showing a greater response with the P solution compared to the MPS (p < 0.05). Conclusion: This study suggests that the SiH lens investigated demonstrated an upregulated response when used with a MPS compared to a P solution whereas the converse is true for the CH lens which showed a reduced response when used with a MPS compared to a P solution. This finding aids in the understanding of the biological underpinnings of manifest corneal inflammatory events during contact lens wear.