Use of liquid e-cigarettes is increasing worldwide, and although nicotine is the primary active component, many products contain various flavorings and additives. Nicotinamide has been identified as an additive in liquid e-cigarettes, but its effects on nicotine dependence are not well understood. This study aimed to evaluate the effects of nicotinamide on nicotine dependence-related behaviors using mice. We established a mouse vapor self-administration paradigm using commercially available liquid e-cigarette cartridges in order to closely mimic human use. Mice were exposed to nicotine vapor (6 mg/mL) alone or nicotine combined with nicotinamide (5, 15, or 30 mg/mL). Following initial food training, mice were trained under a fixed-ratio schedule to self-administer nicotine vapor, and subsequent sessions assessed self-administration responses under exposure to nicotine alone versus nicotine–nicotinamide mixtures. Nicotine vapor at 6 mg/mL produced a significant increase in self-administration behavior. Co-exposure to nicotine and nicotinamide at 15 mg/mL further increased self-administration responses compared with nicotine alone, suggesting an enhancement of nicotine’s reinforcing effects in this mixture form. These findings indicate that nicotinamide may potentiate the dependence liability of nicotine, raising concerns that this commonly used e-cigarette additive could increase the risk of nicotine dependence in users.