Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer’s disease (AD). Ibuprofen reduces amyloid (Aβ) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of Aβ production has not been ruled out. This study shows that ibuprofen reduced Aβ brain levels in rats from exogenously infused Aβ in the absence of altered Aβ production. To determine whether ibuprofen inhibits proamyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Aβ and inflammation-related molecules α- antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor γ) (PPARγ) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1β, which was reduced in these animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Aβ42 production, these observations suggest that ibuprofen reduction of Aβ pathology may not be mediated by altered Aβ42 production. This study presents evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1β and its downstream target ACT).