Chronic arsenic exposure can lead to palmo-plantar keratosis. In the stratum corneum, linoleic acid is responsible for inflammation, keratinization, regeneration etc. The aim of this study was to understand the role of linoleic acid in pathophysiology of arsenical keratosis. Lipid extracts were collected from keratotic lesions of patients, arsenic exposed and non-exposed controls (all seven in number). Linoleic acid levels were estimated by RP-HPLC. The data were expressed as mean ± SE. There was significant (P<0.001) increase in linoleic acid levels (μg/sq.cm) in arsenical keratosis patients (palm = 25.66±4.95; dorsum = 28.25±6.20) compared to arsenic exposed (palm = 2.75±0.85; dorsum = 1.96±0.64) and non-exposed (palm = 1.52±0.61; dorsum = 1.28±0.39) control groups. There was no significant difference (P=0.556) of linoleic acid concentration in non-affected skin of dorsum of the hand (28.25±6.20) compared to palmar sites (25.66±4.95), in patient group. Change in linoleic acid levels of arsenic-exposed control group was not noteworthy (P=1.000) than that of non-exposed controls. This study may contribute a maiden guideline regarding pathophysiology of arsenical keratosis.