Activated microglia and reactive astrocytes invade and surround cerebral β amyloid (Aβ) plaques in Alzheimer's disease (AD), but the role of microglia in plaque development is still unclear. In this study, minocycline was administered for 3 months, prior to and early in Aβ plaque formation in amyloid precursor protein transgenic mice (APP-tg). When minocycline was given to younger mice, there was a small but significant increase in Aβ deposition in the hippocampus, concurrent with improved cognitive performance relative to vehicle treated mice. If APP-tg mice received minocycline after Aβ deposition had begun, microglial activation was suppressed but this did not affect Aβ deposition or improve cognitive performance. In vitro studies demonstrated that minocycline suppressed microglial production of IL-1β, IL-6, TNF, and NGF. Thus, minocycline has different effects on Aβ plaque deposition and microglia activation depending on the age of administration. Our data suggest that this may be due to the effects of minocycline on microglial function. Therefore, anti-inflammatory therapies to suppress microglial activation or function may reduce cytokine production but enhance Aβ plaque formation early in AD. © 2006 Wiley-Liss, Inc.