High school students are maturing physically, psychosocially, and sexually. Some may be unsure of their sexual orientation. The purpose of the study was to determine whether students who self-identified as homosexual-lesbian/gay, bisexual (LGB), and unsure of sexual orientation had more stressful life events (SLEs), perceived stress, bullying victimization, and depressive symptoms as compared to heterosexual peers. Cortisol was examined to determine whether levels were within normal range for age and followed a normal diurnal rhythm. This correlational design included five surveys to assess n = 143 ninth graders. LGB and unsure students had more SLEs, perceived stress, bullying victimization, and depressive symptoms than heterosexual peers. All participants had normal cortisol levels, with the majority having normal diurnal rhythms. School nurses should consider more training about LGB and unsure students. Additional outreach, support, screening, or referrals for LGB and unsure students are warranted if the school nurse suspects depressive symptoms.