INTRODUCTION: To identify pre-treatment clinical variables and hormonal responses predictive of successful spermatogenic response to empiric medical therapy (EMT), then to create a nomogram to guide clinical therapy. MATERIALS AND METHODS: All men who had been treated at our institution with EMT for moderate-severe oligospermia (≤ 10 million sperm/mL) from 2003 to 2014 were included in our study. Men with hypogonadotropic hypogonadism, azoospermia, or those who had varicocelectomy or had received fertility altering medications within 6 months of initiating EMT were excluded, as well as those who did not obtain a follow up semen analysis. Pre-treatment clinical variables, hormonal responses, and spermatogenic responses were assessed. Success was defined by improvements in baseline sperm concentrations as follows: (1) cryptospermia to ≥ 0.3 million/mL, (2) > 100% increase in sperm concentration for men with baseline concentration < 1 million/mL, or (3) a 30% increase in sperm concentration for men with a baseline concentration between 1-10 million/mL. We performed univariate analysis to evaluate for predictors of success. The Wilcoxon rank sum test was used for continuous variables and the Fishers exact test was used for categorical variables. Multivariable logistic regression was then used to build a nomogram. RESULTS: We identified 107 men who were treated with EMT for oligospermia (≤ 10 million sperm/mL) who met our inclusion criteria. Forty-five men (42%) exhibited a poor spermatogenic response to EMT and 62 men (58%) exhibited a good response. Univariate analysis did not identify significant differences in any variable between the two groups. Multivariate analysis did identify predictive combinations which allowed the development of a nomogram with a high concordance index (0.78) for predicting spermatogenic response to EMT. CONCLUSIONS: While none of the individual pre-treatment clinical variables or hormonal responses were predictive of success following EMT, analysis of multiple factors in concert yielded a clinically useful nomogram with a high concordance index.