This prospective study described the trajectory of sexual well-being from before hematopoietic cell transplantation (HCT) to 3 years after in 131 allogeneic and 146 autologous HCT recipients using Derogatis Interview for Sexual Function and Derogatis Global Sexual Satisfaction Index. Sixty-one percent of men and 37% of women were sexually active pre-HCT; the prevalence declined to 51%(P 5.01) in men and increased to 48% (P 5 .02) in women at 3 years post-HCT. After HCT, sexual satisfaction declined in both sexes (P < .001). All sexual function domains were worse in women compared with men (P ≤ .001). Orgasm (P 5 .002) and drive/relationship (P < .001) declined inmen, but sexual cognition/fantasy (P 5.01) and sexual behavior/ experience (P 5 .01) improved in women. Older age negatively impacted sexual function post-HCT in both sexes (P < .01). Chronic graft-versus-host disease was associated with lower sexual cognition/fantasy (P 5 .003) and orgasm (P 5 .006) in men and sexual arousal (P 5.05) and sexual satisfaction (P 5.005) in women. Allmale sexual function domains declined after total body irradiation (P < .05). This study identifies vulnerable subpopulations that could benefit from interventional strategies to improve sexual well-being. © 2013 by The American Society of Hematology.