To date, little is known about genes affecting the interplay of brain and heart activity. Because serotonin (5-HT) is involved in corticovagal neurotransmission, we tested whether the 5-HT transporter polymorphism 5-HTTLPR affects brain-heart covariation. Further, associations with neuroticism/anxiety (NANX) were tested, as anxiety is related to 5-HT and neurogenic changes of heart period (HP). N = 168 participants performed a time-estimation task while EEG and HP were recorded. Brain-heart covariation was measured using time-lagged within-subject correlations of centromedial feedback-evoked single-trial EEG at 300 ms and subsequent changes of HP. EEG-HP correlations were higher in 5-HTTLPR long allele carriers. Moreover, after negative feedback, EEG-HP correlations and feedback-related negativity amplitudes independently correlated with NANX. The results indicate that individual differences in brain-heart covariation relate to 5-HT and NANX.