Cannabinoid receptors CB(1) and CB(2) are primarily expressed in cells of the nervous and immune systems, respectively. Recently, the synthetic CB(1)/CB(2) 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 CB(2) receptors. By reverse transcription-polymerase chain reaction, microglia were found to express both CB(1) and CB(2) receptors. Using additional CB(1)/CB(2) receptor agonists and selective antagonists, we found that CB(2) 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.