Objective To critically examine the safety of T therapy given to postmenopausal women. Design MEDLINE literature review, cross-reference of published data, and review of Food and Drug Administration transcripts. Result(s) Although some retrospective and observational studies provide some long-term safety data, most prospective studies have had a duration of 2 years or less. In addition, with the exception of the female-to-male transsexuals, T was administered in conjunction with estrogens or estrogens and progestins, which confound the interpretation of some of the studies. The major adverse reactions are the androgenic side effects of hirsutism and acne. There does not appear to be an increase in cardiovascular risk factors, with the exception of a lowering of high-density lipoprotein with oral T. There are little data on endometrial safety, and most of the experimental data support a neutral or beneficial effect in regards to breast cancer. There does not appear to be an increased risk of hepatotoxicity, neurobehavorial abnormalities, sleep apnea, or fetal virilization (in premenopausal women) with the physiologic treatment doses of T. Conclusion(s) Except for hirsutism and acne, the therapeutic administration of T in physiologic doses is safe for up to several years. However, prospectively collected long-term safety studies are needed to provide a greater degree of assurance.