We sought to develop an oral treatment for unconjugated hyperbilirubinemia. In the Gunn rat model of unconjugated hyperbilirubinemia, dietary supplementation with the lipase inhibitor orlistat (Orl) or with calcium phosphate (CaP) decreases plasma unconjugated bilirubin (UCB) levels. We determined whether Orl, CaP, or their combination is superior to phototherapy, the conventional treatment, and whether the effects of Orl and CaP are influenced by dietary fat content. Gunn rats were treated with Orl (200 mg/kg chow), CaP (20 g/kg chow), Orl + CaP, or continuous phototherapy (19 muW/cm(2)/nm) during a low-fat (LF) diet (13 energy%) or high-fat (HF) diet (35 energy%). Plasma UCB and fecal fat excretion were measured before, during, and/or at the end of treatment. Orl treatment for 2 weeks (HF diet) reduced plasma UCB concentrations similar to phototherapy (-34% and -28%, respectively); the combination of both was more effective than either treatment alone (-48%; P < .001). After 3 weeks of a HF diet, plasma UCB was 46% lower compared with the LF diet (P < .001). Plasma UCB concentrations were negatively correlated with fecal fat excretion (r = -0.96; P < .001). Irrespective of dietary fat content, 3 weeks of combined treatment (Orl + CaP) decreased plasma UCB by approximately 50% (P < .01) and was more effective than phototherapy (P < .05) at the intensity provided. In conclusion, plasma UCB concentrations in Gunn rats are negatively related to fecal fat excretion and dietary fat content. Orlistat is equally effective as phototherapy for the treatment of unconjugated hyperbilirubinemia in Gunn rats, and combined oral treatment with Orl + CaP is more effective than phototherapy. The present results support the feasibility of an efficient oral treatment of unconjugated hyperbilirubinemia.