The observation that nicotine modulates negative affectivity and has a mood enhancing effect mainly derives from studies conducted in the general population and in clinical samples, mostly in nicotine-deprived subjects. It has been explained by the so called deprivation-reversal hypothesis (i.e., nicotine modulates affect because it alleviates withdrawal symptoms). However, experimental studies suggest that nicotine might modulate different affective functions (e.g., aggressiveness, anxiety) and exert a direct modulating effect on human affectivity. The present paper is a systematic review of the literature aiming at verifying this second hypothesis. A computerized search was carried out (PubMed/Medline 1960-2012). Inclusion criteria were: 1. English language papers published in peer-reviewed journals; 2. experimental/quasi experimental design studies; 3. no deprived adults; 4. inclusion of a control condition; 5. no additional Axis I or II psychiatric disorders. Twenty-one papers met our inclusion criteria. Nicotine was showed to alleviate depression both in smokers and non-smokers, especially if depressed or vulnerable to depression. This effect seemed related to the activation of the dopaminergic brain rewarding system. No clear effect on anxiety was found. Nicotine, thus, seems to exert a direct modulating effect on human mood. Possible limitations of the reviewed studies and future research directions are proposed.