Background: The genetic polymorphism responsible from Gilbert's syndrome is not sufficient for the clinical phenotype to occur in many persons. Additional factors are believed to contribute in pathogenesis. Red cell mass may be such a factor. Methods: We have retrospectively evaluated computer records of all liver function tests assayed between January 2005 and February 2006. The database was screened to find cases with unconjugated hyperbilirubinemia and normal liver enzymes and blood count values on simultaneous assays. The control group for comparison of surrogate markers of total red cell mass comprised of age- and gender-matched persons who had laboratory tests with completely normal results on the same day with the hyperbilirubinemic cases. Gilbert's syndrome cases were found with medical record assessment, and these cases and their control subjects were more strictly assessed. Three different control groups were established for Gilbert's syndrome cases, one of them including healthy blood donors and personnel. Results: In 48,516 otherwise normal laboratory test results, we have found that 491 male subjects and 323 female subjects with unconjugated hyperbilirubinemia had higher hemoglobin, hematocrit, and red blood cell values compared with age-and gender-matched control subjects (P < 0.001 for all comparisons). Twenty-six males who had been followed for Gilbert's syndrome also showed higher hemoglobin, hematocrit and red cell count values in comparison to all control groups. Mean red cell volume value did not differ between the hyperbilirubinemic persons and control groups. Conclusions: Relatively increased red cell mass probably plays a role in the pathogenesis of Gilbert's syndrome.