Testosterone (T) supplementation increases fat-free mass (FFM) and muscle size. Considerable heterogeneity exists in this anabolic response; however, the factors that contribute to variation in an individual's anabolic response to androgens remain unknown.We investigated whether testosterone dose and/or any combination of baseline variables including concentrations of hormones, growth factors, age, measures of body composition, muscle function, muscle morphometry or polymorphisms in androgen receptor could explain the variability in anabolic response to testosterone. Fifty-four healthy young men completed 20 weeks of treatment with both a long acting GnRH agonist (to suppress endogenous T production) and one of 5 doses (25, 50, 125, 300 or 600-mg/week) of testosterone enanthate (TE). Anabolic response was operationally defined as change in whole body FFM (by DEXA), appendicular FFM (by DEXA) and thigh muscle volume (by MRI) during TE treatment. Increasing doses of TE were associated with dose-dependent changes in serum total and free T concentrations, FFM and muscle size. Despite strong correlation between TE dose and changes in FFM and muscle size, there was considerable heterogeneity in individual responses to a given TE dose. We used univariate and multi-variate analysis to identify the subset of baseline measures that best explained the variability in anabolic response to testosterone supplementation. The 3 variable model of TE dose, age and baseline prostate specific antigen (PSA) level explained 67% of the variance in change in whole body FFM. Change in appendicular FFM was best explained (64% of the variance) by the linear combination of TE dose, baseline PSA and leg press strength, while TE dose, log of the ratio of luteinizing hormone (LH) to testosterone (T) concentration (LH/T) and age explained 66% of the variation in change in thigh muscle volume (MRI). The models were further validated by using Ridge analysis and cross-validation in data subsets. Only the model using testosterone dose, age, and PSA was a consistent predictor of change in FFM in subset analyses. The length of CAG tract was only a weak predictor of change in thigh muscle volume and LBM in this small sample. Conclusion: The anabolic response of healthy, young men to exogenous testosterone administration can largely be predicted by the testosterone dose. Further studies are needed to elucidate the genetic basis of natural variation in androgen responsiveness and to test the generalizability of the proposed prediction models.