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Microtubule targeting agents (MTAs) often lead to treatment limiting and life threatening side effects, including chemotherapy-induced peripheral neuropathy (CIPN). The frequency of severe CIPN varies among different MTAs. Since the microtubule binding interactions and mechanisms of action also vary among MTAs, we hypothesized that these distinct mechanisms may underlie the variability in frequency of severe CIPN. Using a two-week, maximum tolerated dose model, we morphologically and biochemically analyzed sciatic nerves from mice treated with either paclitaxel or eribulin. These drugs differ in their manner of microtubule binding and mechanisms of action and reports indicate paclitaxel also induces a higher frequency of severe CIPN than does eribulin. Morphologically, paclitaxel increased the frequency of observed signs of axon degeneration more significantly than did eribulin. Alternatively, eribulin but not paclitaxel induced occasional myelin 'halo' structures. Biochemically, paclitaxel, and eribulin both induced α-tubulin expression (~1.9- and ~2.5-fold, respectively) and tubulin acetylation, a marker for microtubule stability, (~5- and ~11.7-fold, respectively). Eribulin but not paclitaxel-induced EB1 expression ~2.2-fold while paclitaxel but not eribulin mildly suppressed EB3 expression. Both EB proteins are associated with microtubule growth. Eribulin's combination of relatively mild deleterious morphological effects coupled with more potent biochemical changes promoting microtubule stability and growth in mice correlate with lower frequencies of severe CIPN in humans. We suggest that these eribulin-induced effects create a relatively stable microtubule network that compensates, in part, for the toxic anti-cancer effects of the drug, leading to fewer reported incidences of CIPN than for paclitaxel. [ABSTRACT FROM AUTHOR]