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PURPOSE: To evaluate the effect of a low-molecular weight hyaluronic acid derivative (HAD), incorporated into a multipurpose disinfecting solution (MPS), on symptoms and signs of comfort during contact lens wear. METHODS: Contact lens wearers with dry eye symptoms (CLDEQ-8 ≥ 12) were enrolled across three clinical trials. Participants wore comfilcon A contact lenses and used cleadew MPS with or without HAD for eight weeks, with monthly lens replacement. The first trial compared HAD-containing MPS with habitual lens care, the second compared non-HAD MPS (containing identical excipients) with habitual care, and the third directly compared HAD and non-HAD MPS. Follow-up assessments included CLDEQ-8, tear meniscus height, non-invasive tear break-up time (NITBUT), meibomian gland morphology, lipid layer thickness (LLT), tear volume (phenol red thread test), and ocular surface health assessed by slit-lamp examination and fluorescein staining. RESULTS: Twenty-three participants used HAD MPS and eighteen used non-HAD MPS. In all trials using HAD-containing MPS, CLDEQ-8 scores improved significantly after eight weeks (P ≤ 0.003; mean reduction ≥7.7). No significant comfort improvement was observed with non-HAD MPS (P ≤ 0.13; mean reduction ≤3.3). These symptom improvements were generally not accompanied by significant changes in tear stability, tear volume, LLT, or ocular staining. Notably, participants previously wearing daily disposable lenses and reporting discomfort demonstrated significant improvement in CLDEQ-8 scores with HAD MPS (P < 0.008), with a trend toward normalization of symptoms. CONCLUSIONS: HAD-containing MPS improves contact lens comfort, including in previously symptomatic daily disposable lens wearers. This benefit may relate to improved lens surface wettability and reduced friction, warranting further investigation.