Cell recognition molecules of the L1 family serve important functions in the developing and the mature nervous system. Mutations in genes encoding the L1 family members close homolog of L1 (CHL1) and NgCAM-related cell adhesion molecule (NrCAM) have been found to alter connectivity and morphology of several brain regions. In order to emphasize similarities and differences of these two structurally related molecules, null mutants for CHL1 and NrCAM were directly compared with respect to axonal guidance in the hippocampus and the olfactory bulb and the sizes of the ventricular system and the cerebellar vermis using a combined structural magnetic resonance imaging (MRI) and histological approach. The results demonstrate that the absence of CHL1 leads to aberrant hippocampal mossy fiber projections whereas in both mutants, CHL1 and NrCAM, the guidance of the olfactory nerve projections is disturbed. Both mutations also alter the size of the ventricular system and the vermis with a specific profile of changes and partially opposite effects in each of the mutants. CHL1/NrCAM double-mutant mice do not show any enhancement of the single mutant's phenotype but balance the opposing effects on the ventricular system. In summary, the results show that CHL1 and NrCAM both affect axonal guidance and the anatomy of the ventricular system and the cerebellar vermis but act differently on these processes.