Cannabinoid receptors CB1 and CB2 are primarily expressed in cells of the nervous and immune systems, respectively. Recently, the synthetic CB1/CB2 agonist WIN55,212-2 was found to suppress replication of HIV-1 in microglial cell cultures. The present study was undertaken to test the hypothesis that WIN55,212-2's antiviral effect is mediated via CB2 receptors. By reverse transcription-polymerase chain reaction, microglia were found to express both CB1 and CB 2 receptors. Using additional CB1/CB2 receptor agonists and selective antagonists, we found that CB2 receptors are involved in WIN55,212-2's antiviral activity and surprisingly that the CB 1 receptor-selective antagonist SR141716A behaved as an agonist in these brain macrophages.