Juvenile channel catfish (14.4 g average initial weight) were fed diets supplemented with a purified nucleotide mixture for 8 weeks. The mixture consisted of five nucleotides supplied on an equal basis as disodium salts at combined concentrations of 0 (control), 0.1%, 0.3%, 0.9% or 2.7% of diet. Addition of nucleotides to diet produced a dose-dependent reduction in survival of channel catfish to Edwardsiella ictaluri. Although the reasons are unclear, the high levels of nucleotides supplemented in this study may have contributed to the decrease in disease resistance, and this decrease appeared to be unrelated to the innate immune (unaffected) and specific antibody (enhanced) responses. Stress resistance increased with a corresponding amelioration of the immunosuppressive effects of the stress response on non-specific immunity (lysozyme and bactericidal activity) as nucleotides increased in diet. Use of exogenous nucleotides as a prophylactic treatment before culture-related stress exposure may prove beneficial by decreasing the immunosuppressive effects of stress but not in prevention of ESC.