Lidocaine is a sodium channel blocker that is typically used for topical pain relief. When administered intravenously, lidocaine also has a demonstrated analgesic effect in neuropathic pain patients. It is unclear, however, whether lidocaine operates by suppressing peripheral nerve conduction or through more central mechanisms. Previous work has shown that intravenous lidocaine affects mood as well as pain, suggesting effects in the central nervous system. If lidocaine causes analgesia through central routes, individual differences in mood may predict response to the drug. In this study, we tested the hypothesis that baseline mood would predict individual analgesic response to intravenous lidocaine. 57 patients were seen at the Stanford Pain Clinic. Patients were given a saline placebo followed by 3 µg/ml and 5 µg/ml of lidocaine by computer-controlled transfusion. Patients completed the Brief Profile of Mood States (POMS), and a Visual Analog Scale (VAS) rating of pain at baseline, placebo and after each dose. Data were analyzed using a repeated measures General Linear Model (GLM). The Depression/Dejection subscale of the POMS emerged as a significant predictor of lidocaine response, as measured by the VAS (F(3) = 5.78, p = 0.004). Individuals with higher baseline levels of depression showed significantly greater analgesic response to the drug. Because baseline depression scores also correlated positively with baseline VAS pain (r = 0.348, p = 0.009), we conducted a second GLM to test the predictive ability of depression after controlling for baseline pain. The GLM revealed that the greater analgesic effect on more depressed individuals was not due to their greater levels of baseline pain. Furthermore, depression was not influenced by lidocaine infusion (p=0.325). These results suggest that intravenous lidocaine provides more effective pain relief for more depressed individuals, but through mechanisms separate than relief of their depression.