Morphine, used clinically for pain management for its potent analgesic effects, has a high abuse potential. In this study, we utilized the conditioned place preference (CPP) paradigm and tail-flick latency to examine the effects of the endotoxin lipopolysaccharide (LPS) on sensitivity to morphine. Rats were pretreated with either LPS (250 μg/kg) or saline, followed by either a higher dose of LPS (2 mg/kg) or saline. Rats were then given either morphine (3.5 mg/kg) or saline every other day for 6 d starting 72 h after the last dose of LPS or saline as part of the conditioning phase. Drug preference was assessed during the postconditioning phase. LPS-treated rats displayed a stronger and prolonged morphine preference during the 20 d of extinction testing. A parallel analysis revealed that tail-flick latencies were significantly longer in LPS-treated rats. Together, our data indicate that systemic infections can increase sensitivity to morphine both physiologically and behaviorally.