<p>Short-pulsed lasers provide safe and efficacious treatment of pigmented lesions by setting irradiation parameters based on immediate whitening resulting from vacuolization. However, visual observation of this phenomenon as an irradiation endpoint is subjective and makes it difficult to assess the depth to which the light response is induced inside the skin. To quantitatively understand the dependence of the light response on irradiation parameters, this study analyzes the spatial distribution of light-melanosome interaction based on the fluence distribution in an optical phantom. Nanosecond laser irradiation was applied to an optical phantom with a uniform distribution of melanosomes with varying irradiation fluence and spot size. The observed spatial distribution of the light-melanosome response was compared with the fluence distribution in the phantom calculated from numerical simulations. The resulting relationship between irradiation parameters and optical response showed that cavitation increased rapidly at an in-phantom fluence of 1.37 J/cm<InlineEquation ID="IEq1"> <EquationSource Format="TEX">\(^2\)</EquationSource> <EquationSource Format="MATHML"><math> <mmultiscripts> <mrow /> <mrow /> <mn>2</mn> </mmultiscripts> </math></EquationSource> </InlineEquation> and reached a saturated state at the threshold fluence for melanosome disruption. Additionally, increasing the spot size promoted cavitation at greater depths as well as increasing irradiation fluence, highlighting the need to consider both irradiation fluence and spot size for treatment depth control. The experimental results suggest the potential for quantitative control of optical responses in laser treatment of pigmented lesions. Further validation by experiments on samples with spatial distribution of cutaneous melanosomes is required.</p>