Mice lacking both alleles of the LIM-homeobox gene Lhx7 display dramatically reduced number of forebrain cholinergic neurons. Given the fact that sex differences are consistently observed in forebrain cholinergic function, in the present study we investigated whether the absence of LHX7 differentially affects water maze performance in the two sexes. Herein we demonstrate that LHX7 null mutants display a sex-dependent impairment in water maze, with females appearing more affected than males. Moreover, neurotrophin assessment revealed a compensatory increase of brain-derived neurotrophic factor and neurotrophin 3 in the neocortex of both male and female mutants and an increase of nerve growth factor levels only in the females. Nevertheless, the compensatory increase of cortical neurotrophin levels did not restore cognitive abilities of Lhx7 homozygous mutants. Finally, our analysis revealed that cortical neurotrophin levels correlate negatively with water maze proficiency, indicating that there is an optimal neurotrophin level for successful cognitive performance.