Rheumatoid Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy affecting peripheral visual field and usually culminates in complete blindness. Among mutations in 73 genes implicated in RP pathogenesis, those in RP1 gene are inherited in autosomal recessive or dominant fashion. In RP Sicilian patients, we detected 3 polymorphisms in RP1 exon 4 hotspot region, not known to be associated with RP disease. Here, their frequency in Sicilian populations was assayed in order to detect possible association with RP. Samples from 220 unrelated healthy donors born and living in Sicily for at least two generations and 50 RP patients from Messina were screened. Frequencies of all three polymorphisms in RP patients from Messina were about twice those observed in the healthy controls from the same town and the overall Sicilian population. An association between 3 polymorphisms and RP was suggested, although their role in other related disorders cannot be excluded.