Abstract Previous murine studies have implicated acid sphingomyelinase (aSMase)‐generated subcellular microvesicle particles (MVP) in photosensitivity. Objective: The current double‐blinded placebo‐controlled studies examined if a single localized ultraviolet B radiation (UVB) treatment generated more MVP in human subjects with self‐identified photosensitivity versus normal controls. A topical 4% formulation of the aSMase inhibitor imipramine applied immediately after UVB blocked the MVP release and erythema responses. Erythema responses at 24 and 72 h in response to multiple UVB fluences and minimal erythema doses (MED) at 24 h and effects of imipramine were also tested. Small cohorts of 10 adult self‐identified photosensitive subjects and 12 controls were enrolled in these pilot studies which revealed increased levels of skin MVP in UVB‐treated photosensitive subjects over controls which correlated with MED values. Moreover, post‐UVB application of imipramine blunted UVB‐induced MVP responses as well as tended to diminish erythema levels at 4 h but not at 24 or 72 h in photosensitive patients. Though limited by low numbers of self‐identified subjects, these pilot studies provide some support for the hypothesis that MVP could be involved in multiple types of human photosensitivity responses and suggest aSMase inhibition as a potential therapeutic strategy.