Previous studies on the use and abuse of diet pills and related weight loss substances have frequently noted that such use tends to be more prominent among females. However, the majority of previous studies have focused on the use of diet pills by adolescents. In this study, a nationally representative sample, drawn from the 2012 National Survey on Drug Use and Health, is used to examine the use of diet pills and xanax (a prescription drug often misused for weight loss purposes) among adults. This study also focuses upon the differences in predictors of such substance use among females and males. Using a foundation of self-determination theory (SDT), this study posits that individuals will be more likely to abuse diet pills and xanax when their needs for competence, autonomy, and relatedness are not being met. In the analyses, females are shown to be more likely than males to use diet pills, yet males report a higher rate of consumption of xanax, as compared to females. Among the various measures of well-being, depression appears to be a salient predictor of males’ use of both substances, yet not among females. Males also appear to be more likely to use both substances as a function of age, while this association is less influential among females. The meanings and implications of these findings for both researchers and practitioners are discussed.