Females perform better in certain memory-related tasks than males. Sex differences in cognitive performance may be attributable to differences in circulating oestrogen acting on oestrogen beta receptors (ERbeta) which are prevalent in brain regions such as the hippocampus, frontal lobe and cortex that mediate cognitive functions. Since soya isoflavones are known to activate ERbeta, chronic isoflavone supplementation in males may improve cognitive performance in memory-related tasks. A 12-week double-blind, placebo-controlled cross-over trial was conducted in thirty-four healthy men to investigate the effect of isoflavone supplementation on cognitive function. Volunteers were randomised to take four capsules/d containing soya isoflavones (116 mg isoflavone equivalents/d: 68 mg daidzein, 12 mg genistein, 36 mg glycitin) or placebo for 6 weeks, and the alternate treatment during the following 6 weeks. Assessments of memory (verbal episodic, auditory and working), executive function (planning, attention, mental flexibility) and visual-spatial processing were performed at baseline and after each treatment period. Isoflavone supplementation significantly improved spatial working memory (P = 0.01), a test in which females consistently perform better than males. Compared with placebo supplementation, there were 18 % fewer attempts (P = 0.01), 23 % fewer errors (P = 0.02) and 17 % less time (P = 0.03) required to correctly identify the requisite information. Isoflavones did not affect auditory and episodic memory (Paired Associate Learning, Rey's Auditory Verbal Learning Task, Backward Digit Span and Letter-Number Sequencing), executive function (Trail Making and Initial Letter Fluency Task) or visual-spatial processing (Mental Rotation Task). Isoflavone supplementation in healthy males may enhance cognitive processes which appear dependent on oestrogen activation.