This study examined the influence of family rejection, social iso- lation, and loneliness on negative health outcomes among Thai male-to-female transgender adolescents. The sample consisted of 260 male respondents, of whom 129 (49.6%) were self-identified as transgender and 131 (50.4%) were self-identified as cisgender (nontransgender). Initial multivariate analysis of variance indi- cated that the transgender respondents, when compared to the cis- gender respondents, reported significantly higher family rejection, lower social support, higher loneliness, higher depression, lower protective factors (PANSI-positive) and higher negative risk factors (PANSI-negative) related to suicidal behavior, and were less cer- tain in avoiding sexual risk behaviors. Multiple regression analysis indicated that the exogenous variables of family rejection, social isolation, and loneliness were significant predictors of both trans- gender and cisgender adolescents’ reported levels of depression, suicidal thinking, and sexual risk behaviors. The implications of these findings are discussed.