A number of pathological missense mutations of L1CAM have been shown to disrupt L1-L1 homophilic binding and/or affect surface expression. To investigate whether these mutations disrupt L1-mediated neurite outgrowth, cerebellar neurons from L1 knockout mice are transfected with WT human L1 or L1 mutant constructs, and grown on an L1 substrate. Various parameters of neurite growth are quantified. Most L1 mutations do not affect neurite length significantly but several mutations cause a significant decrease in branching. Comparison of these data with data on L1 expression levels and homophilic binding strength show that changes in neurite growth cannot be simply explained by reductions in either of these parameters. Our results suggest that a coreceptor is involved in L1-mediated neurite outgrowth. Some pathological mutations have little effect on L1 mediated neurite growth, so it is unlikely that a failure of L1-mediated neurite outgrowth is the principle cause of brain defects in patients with L1 mutations.