Novel events are unpredictable and accidental. The ability to detect and cope with unpredictable events is fundamental for adapting to a rapidly changing environment and ensuring survival of the organism. In life and laboratory settings, novel events are usually infrequent but emotionally relevant, and thus accompanied by affective responses such as interest or surprise. Behavioral and neuroimaging studies have reported gender differences in brain responding to emotion–relevant infrequent stimuli. Novel events, whether emotionally salient or neutral, are biologically important, because the occurrence is sudden, with unpredictable meaning and perceptually salient. Although females are known to show enhanced sensitivity to emotional stimuli and infrequent stimuli (both of which are biologically significant), it remains unknown whether females and males differ in their processing of emotionally neutral, novel stimuli. The present study used modified three–stimulus oddball tasks and event related potential to investigate neurophysiological mechanisms of possible gender effect in neural processing of novel events. To maximize ecological validity and to test whether this enhanced processing of novelty in females was independent of the established brain sensitivity of females to infrequent stimuli, the study matched the novel and standard stimuli in onset frequency, and both of them were task–irrelevant. In this experiment, the target stimulus (20%, a natural scene of a cup) and the standard stimulus (40%, a natural scene of a bench) were kept constant, whereas a set of emotionally neutral, non–repeated pictures were used as the novel stimuli (40%). Subjects were required to press a key for a target stimulus. The distracters included a non–novel standard stimulus and a set of novel stimuli. The standard and novel stimuli were matched for physical attributes, different only in novelty. 18female (19–23years; mean = 21.11 years) and 18 male (19–25 years; mean = 21.25 years) college students participated in the experiment as paid volunteers. This experiment examined stimulus (standard, novel) by gender (male, female) interaction effects for the averaged amplitudes in 130–700 ms time window, by conducting a repeated measures ANOVA (stimuli as the repeated factor while gender was the between–subjects factor).ERP results demonstrated there was significant novelty effects in the early phase (130ms). Whether males or females, the novel stimulus induced the larger late positive component (LPC) amplitudes of the 300–300ms than the standard stimulus. Most importantly, females displayed a sustained novelty effect in the late positive component (LPC) amplitudes of the 500–700ms, but not males. Thus, the analysis results showed enhanced processing of stimulus novelty in females than in males in the 500–700ms of the LPC time window. Therefore, the current experiments revealed both of males and females processed the novel stimulus, but females might spend more time to process the novel stimuli than male. There may be a female advantage in ruminating salient events.