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Aims: The aim of this study was to evaluate various reaction pattern of skin diseases in Oman using immunofluorescence and light microscopy investigation only. Methodology: A total of 187 skin biopsies were retrospectively analyzed at Sultan Qaboos University Hospital between 2006 and 2010. The presence of immune-reactants (IgA, IgG, IgM, C3 and Fibrin) and the final diagnosis by heamatoxylin and eosin stain in skin biopsy were investigated. Results: Females (59.36%) predominated over males (40.64%). Adults, aged between 26 and 44years, had the highest cases of skin diseases. The most frequent diagnosis were vesiculo bullous (n=71), lichenoid (n=69), vasculopathic (n=19) and epidermal disease (n=13) groups. Vesiculo bullous group showed different deposits of IgA, IgG, IgM, C3 and Fibrin with 19.72%, 23.94%, 8.54%, 21.13%, 11.27%, respectively. Psoriasis (n=2) and reactive condition (n=1) groups were the lowest pattern of skin diseases. IgG was positive in one case of psoriasis and there is a total absence of positive immune-reactants in epidermal disease and reactive condition groups. Original Research Article British Journal of Medicine & Medical Research, 4(31): 5033-5042, 2014 5034 Conclusion: Based on the findings of this study, this retrospective study showed that vesiculo bullous group followed by lichenoid group were the most common skin disease groups detected by immunofluorescence in Oman, while psoriasis and reactive condition groups were the least frequent. Although all immune-reactants were low in their positivity, they were an important component in the final diagnosis of skin biopsies.