The purpose of this secondary analysis is to continue to explore the association between SMS indicators and substance use, while attempting to examine the possibility that depression may account for gender disparities within the association between SMS and substance use. This study used data from the National Longitudinal Study of Adolescent to Adult Health or Add Health. This study utilized data from the Waves I and IV of the restricted-use dataset. Stratified linear regression and logistic regression models were used to determine whether sexual minority status predicted alcohol and drug use, net of demographic covariates, and if these effects were different for women and men as well as for individuals with high or low scores on a depression inventory. Across all three-substance use outcomes, the results of the demographic covariates were fairly consistent with results reported in the literature. Overall the findings regarding males supported the current literature showing no significant difference between SMS males and heterosexual male substance use. The exception was men who have sex with both men and women and scored higher on the CESD were more likely to report past-year drug use relative to men who reported having sex only with women. Also consistent with current literature, SMS women reported higher levels of alcohol and drug use relative to their heterosexual counterparts. In contrast, women who identified as being lesbian or bisexual reduced the risk of past-year drug use regardless of CESD scores, and women who identified as being lesbian or bisexual and had low scores on the depression inventory reported lower past-year cannabis use than those women who identified as heterosexual. Another notable finding in this study is that sexual abstinence or asexuality appears to be a protective factor against substance use. The findings in this study may mean that SMS woman are actually the driving factor behind the evidence that the LGBT community is more likely to engage in substance use. This could change the focus of the prevention and interventions that are employed by social work and public health professionals when addressing the LGBT community.