The effect of lead exposure on cellular immunity, hematology, and reproductive and body condition in mature cotton rats (Sigmodon hispidus) was examined. Two groups of 36 cotton rats each were exposed to 0, 100, or 1,000 ppm lead in drinking water for either 7 or 13 weeks, between 31 August and 2 December 1990. Specific and non-specific cell mediated immunity was assessed by measuring splenocyte proliferative responses to polyclonal mitogens (Concanavalin A and Pokeweed mitogen), in vivo 24-hr delayed type hypersensitivity, metabolic activity of peritoneal macrophages, spleen mass and cellularity, and immune organ development. General physiological condition was assessed from hematological, morphological, and reproductive measures. Immune function was sensitive to lead exposure based on depressed proliferative responses of cultured splenocytes, smaller popliteal lymph nodes, and larger spleens among cotton rats receiving 1,000 ppm lead. Spleen mass was reduced in cotton rats receiving 100 ppm lead. Total leukocytes, lymphocytes, neutrophils, eosinophils, total splenocyte yield, packed cell volume, hemoglobin, and mean corpuscular hemoglobin were sensitive to lead exposure. Effects of lead exposure on general condition and reproductive parameters included reduced mass of liver, seminal vesicles, and epididymes in males following a 7-week exposure. Histopathologic changes reflected lead toxicity and included altered renal proximal tubular epithelium, renal intranuclear inclusions, and in some cases, lowered numbers of sperm and developing follicles. In general, lesions were more pronounced with increased lead concentration and longer exposure.