Caffeine, in addition to being a food constituent, is also a common analgesic adjuvant that is used in combination with aspirin in certain over-the-counter preparations. Caffeine has previously been shown to significantly improve certain aspects of human performance, particularly sustained vigilance, when administered in low and moderate doses (32 to 256 mg). We therefore attempted to determine whether caffeine, in the dose (64 mg) found in some over-the-counter drugs, retains this beneficial property when combined with aspirin. We also measured self-reported mood state, using various standardized questionnaires, since caffeine has been reported to have both beneficial and adverse effects on alertness and anxiety. We observed that caffeine (64 mg), when added to aspirin (800 mg), significantly improves vigilance performance and increases self-reported efficiency when compared with either placebo or aspirin alone. As previously reported, this caffeine dose alone significantly increased vigilance and decreased reaction time. No adverse effects of caffeine were detected on any of the parameters that were assessed. This study therefore demonstrated that the addition of caffeine to aspirin, in a dose commonly employed in over-the-counter drugs, has significant beneficial consequences with respect to mood and performance.