To determine whether an individualized dose titration regimen (ID) for adult GH replacement therapy would have similar efficacy and better tolerability than a fixed body weight-based dosing regimen (FD), 387 adults with GH deficiency were randomized to FD (n = 200) or ID (n = 187) for 32 wk. In FD, subjects received sequentially 4, 8, and 12 μg/kg·d GH. ID was started at 0.2 mg/d and increased by 0.2-mg/d increments, based on clinical and serum IGF-I responses, to a maximum of 0.8 mg/d. Increases (mean ± sd) in serum IGF-I were similar in both groups (FD, 110.2 ± 87.8 vs. ID, 99.6 ± 77.7 μg/liter, P = 0.20) despite higher final GH doses in FD (0.70 ± 0.32 vs. 0.54 ± 0.22 mg/d, P < 0.001). Favorable changes in several efficacy measures were observed with no significant differences between the FD and ID groups: lean body mass increased; health-related quality of life improved; and abdominal fat mass, hip circumference, sum of skinfolds, and total and low-density lipoprotein cholesterol decreased. The decrease in fat mass was greater with FD than ID for men (−2.7 ± 2.7 kg vs. −1.8 ± 2.5 kg, P = 0.04) but not for women (−2.1 ± 2.4 vs. −2.0 ± 3.8 kg). The change in waist circumference was greater with FD than ID for women but not for men. There was a significant reduction of systolic blood pressure in ID but not in FD. The adverse event profile was similar between FD and ID except that ID had a lower occurrence of peripheral edema (9.1% vs. 16.5%, P = 0.03) and rash (1.1% vs. 5.5%, P = 0.02) than FD. In summary, the use of ID resulted in improved tolerability and similar efficacy compared with FD. We conclude that GH replacement therapy should be initiated at a low dose and titrated to a dose producing maximal benefits without adverse side effects and an IGF-I level within the age- and sex-adjusted normal range.