Recent studies indicating that some nonsteroidal anti-inflammatory drugs (NSAIDs) selectively modulate γ-secretase cleavage of amyloid precursor protein (APP) while sparing Notch processing have generated interest in discovery of novel γ-secretase modulators with the “NSAID-like” efficacy profile. The objective of the present studies was to compare the efficacy of a subset of NSAIDs with previously reported classical γ-secretase inhibitors LY-411575 [N²-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N¹-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide]and DAPT [N-[N- (3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester] in Tg2576 mice. Flurbiprofen (10 and 25 mg/kg/day) was overtly toxic and elicited significant (but nonselective) reductions in both Aβ(1-40) and Aβ(1-42) in the plasma in one of two studies. Flurbiprofen also produced a small reduction in Aβ(1-40) in the cortex at 25 mg/kg/day but did not affect Aβ levels in hippocampus or cerebrospinal fluid. Ibuprofen and sulindac sulfide were neither overtly toxic nor efficacious at doses up to 50 mg/kg/day. The effects of NSAIDs LY-411575 and DAPT were tested in guinea pig embryonic neuronal cultures to determine whether the selective reductions in Aβ(1-42) observed in cell lines overexpressing human mutant APP can be reproduced in a neuronal model of physiological Aβ production and secretion. Flurbiprofen and sulindac nonselectively reduced Aβ(1-40) and Aβ(1-42) at concentrations ≥125 μM, although cytotoxicity was noted at ≥250 μM sulindac. Ibuprofen had no effect at concentrations up to 500 μM. In contrast, DAPT and LY-411575 potently and completely inhibited Aβ(1-40), Aβ(1-42), and Aβ(1-38) in the absence of cytotoxicity. The divergence of the present data from published reports raises the need to examine the conditions necessary to perceive selective Aβ(1-42) reduction by NSAIDs in neuronal tissue.