This study examined the influence of family rejection, social isolation, 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 indicated that the transgender respondents, when compared to the cisgender 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 certain 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 transgender and cisgender adolescents' reported levels of depression, suicidal thinking, and sexual risk behaviors. The implications of these findings are discussed.