In the present work, we investigated the short- and long-term effects of a single systemic injection of rat recombinant interleukin-2 on weight, food intake, and brain stimulation reward thresholds elicited from the ventral tegmental area. An inverted U-shaped dose-function was obtained with 0.5 microg producing the greatest increases in the threshold for rewarding brain stimulation which were sustained during the month long tests. No differences between groups in terms of maximum response rates, a measure of performance, were observed. Although all injected groups showed a minor decline in the rate of weight gain over time, percent efficiency of food utilization (percent weight gain/food intake) was the same across groups, suggesting that metabolic function was not affected by the cytokine. In animals with bilateral ventral tegmental area implants, there was no consistent correspondence between the threshold change obtained from ipsilateral stimulation and that associated with the contralateral site; side-to-side differences ranged from 0 to 100%, suggesting a specific interaction between cytokine activity and the locus of rewarding brain stimulation. These data suggest that peripheral IL-2 significantly modifies hedonic processes arising from medial forebrain bundle stimulation in a long-term manner. We further suggest that since this modulation appears to be notably site-specific, IL-2 receptors or its metabolites may not be evenly distributed within the medial forebrain bundle.