Cyclooxygenase-2 (COX-2) is constitutively expressed in the macula densa of several laboratory animal species where it is considered to play a physiologic role in the regulation of basal renal function. Pertubations to normal homeostasis is shown to be associated with the upregulation of COX-2 in the macula densa of rats and dogs. In contrast, COX-2 has not been detected in the macula densa of normal adult human and non-human primate kidneys, suggesting a less prominent role of this isoform in normal renal function in these species. In this study, we characterized COX-2 expression in human kidneys collected from subjects with a clinical history indicative of compromised renal function associated with diabetic nephropathy (DN), hypertension, and congestive heart failure (CHF). COX-2 expression was evaluated by immunohistochemistry using isoform-specific antibodies and in situ hybridization. No COX-2 protein or mRNA was observed in the macula densa of normal kidneys (n= 11), whereas slight to moderate COX-2 expression was present in the macula densa of 7/15 subjects (46%) with DN, 5/11 (46%) subjects with hypertension, and 3/10 subjects (30%) with CHF. These results indicate that COX-2 is variably induced in the macula densa of the human kidney in compromised renal conditions and that COX-2-mediated prostaglandins may be involved in maintaining adequate renal functions in some patients with DN, hypertension, and CHF. This variability may be related to individual clinical status or synthesis of vasodilatory prostaglandins by cyclooxygenase-1 (COX-1).