Neonatal jaundice is the result of increased bilirubin (BR) production and an immature BR conjugation and excretion system in the liver. Severe hyperbilirubinemia is currently being treated with phototherapy or exchange transfusion; however, these procedures only eliminate BR after it has been produced. The prevention of jaundice through the inhibition of BR formation is a preferable strategy. Heme oxygenase (HO), consisting of the inducible HO-1 and the non-inducible HO-2, is the rate limiting enzyme for the equimolar production of BR and carbon monoxide (CO) from the catabolism of heme. Synthetic metalloporphyrin derivatives of heme (MPs) have been shown to competitively inhibit HO in vivo and suppress hyperbilirubinemia. However, no systematic studies have been performed to evaluate whether the two isozymes are differentially sensitive to inhibition by specific MPs. If so, this would allow specific targeting for inhibition of the inducible (i.e. hemolysis) or non-inducible (basal level) processes. We determined for the deutero- (DP), proto- (PP), meso- (MP), and deuteroporphyrin bis glycol-(BG) porphyrins with zinc (Zn), tin (Sn), chromium (Cr) and no metal as the central atoms, the concentration of each needed for 50% inhibition (150) of HO-1, predominant in spleen, and HO-2, predominant in brain, activities in 13,000×g rat tissue supernatant. HO activity was determined through gas chromatographic measurements of CO generated after 15 min incubation at 37°C of tissue preparation (4mg wet weight) with 50μM heme and 1500μM NADPH. The results show that, even though the isozymes differ vastly in molecular and biochemical properties, 150 of both isozymes occurred most effectively with SnMP, the same ring substituent for a given metal, and the same metal for a given ring substituent. In addition, both isozymes had a near identical order of inhibitor potency. However, the most striking finding was that brain HO-2 sensitivity to inhibition was greatest for SnPP (9-fold) when compared to that of spleen HO-1. Thus SnPP appears to be most suitable for inhibiting HO-2 activity without substantially affecting that of HO-1. Conversely, there exist MPs, such as the Zn compounds, that are less inhibitory for HO-2. Thus, although BR production is due to the activity of HO-1 and HO-2, the inhibition of HO-1 with a relative sparing of HO-2 activity may provide an alternative approach to the treatment of hemolytic disease. These findings may be of physiologic and pharmacologic importance when MPs are considered for use as potential drugs to modulate excessive neonatal hyperbilirubinemia.