Mannose binding lectin (MBL) is known to interact directly with mannose N-linked glycans on the HIV-1 gp120 envelope and with beta amyloid (bA). We hypothesized that MBL unique interactions with both gp120 and bA, in HIV encephalitis (HIVE), and with bA in Alzheimer's disease (AD), facilitate immune complex (IC) deposition and neuroinflammation. Post-mortem brain frontal cortex tissues obtained from California NeuroAIDS Tissue Network and Alzheimer's Disease Research Center were evaluated for the expression and colocalization of MBL, bA, gp120 and monocyte chemoattractant protein -1 (MCP-1) in HIV- controls (n=5), in those with and without HIVE (n=15 each) and AD cases (n=10) using double immunofluorescence and confocal microscopy. Cellular fractionated tissue from frontal cortex of those with and without HIVE and with and without AD was evaluated for MBL and bA expression via western blot. Expression of MBL and bA was enhanced twofold each (p<0.01) and colocalization of the two proteins was found to be increased 1.5 fold (p<0.05) respectively in HIVE vs. nonHIVE brain. Also, a 1.7 fold increased colocalization of MBL, bA and gp120 ICs, (p< 0.01) was observed in HIVE vs. nonHIVE cases. Almost tenfold increase of MBL-bA and eightfold increase in MBL- bA-MCP-1 ICs were observed in AD vs. AD- cases (p<0.01 each). Older individuals with HIVE showed higher MBL-bA deposits (p<0.05 each). HIV- and healthy AD- control showed no cytosolic MBL compared to those with and without HIVE and those with AD. bA localized in membrane fraction was found to be increased 1.3 fold when comparing those with and without HIVE to HIV- control. Increased expression and novel interactions of MBL with gp120 and bA proteins potentially elicit complement mediated IC deposition and inflammation in HIV neuropathogenesis and AD