In this study, we evaluated and compared the pharmacodynamics of paclitaxel (PTX) in human A549 NSCLC cells grown as monolayers or as three-dimensional histocultures. Growth inhibitory effects were determined after incubating cells in drug free medium until 96 hr post drug exposure initiation. Cell cycle arrest and apoptosis were measured by flow cytometry. The growth inhibition induced by PTX was significantly different in monolayers and histocultures, and PTX showed significantly less cytotoxicity in histocultures where large resistant fractions were observed. Moreover, although PIX induced significant $G_{2}/M$ arrest followed by apoptosis in monolayers in a drug concentration-dependant manner, $G_{2}/M$ arrest was not elicited in histocultures. However, apoptotic cells appeared from the $G_{2}/M$ phase in histocultures. In this study, we provide first evidence that PIX in three-dimensional histocultures, does not induce $G_{2}/M$ arrest, but rather that it induces $G_{2}/M$ phase specific apoptosis. Overall, our data demonstrate different pharmacodynamics of PTX in traditional monolayer and three-dimensional histocultures.