Objective: Testosterone therapy (TTh) may reduce morbidity/mortality in men with adult-onset testosterone deficiency (TD), though some cardiovascular safety concerns remain. Increased hematocrit (HCT), a recognized effect of therapy, may be associated with cardiovascular disease and mortality. We examined HCT change (Δ) in men prescribed/not prescribed testosterone, and associations with mortality. Methods: We analyzed data from a prospective registry study with adult-onset TD patients: 353 men given testosterone undecanoate (TU) and 384 opting against TTh. Change in HCT after 12, 48, 72, and 96 months of TU and at final assessment was compared (nonparametric tests). The association between baseline HCT, ΔHCT, and mortality was studied using logistic and Cox regression. Results: HCT increased significantly (median change at final assessment: +5.0%) in men on TTh. HCT was higher (p = 0.021, rank-sum test) in those alive than in those who died, although median values were identical (49.0%). Baseline HCT and ΔHCT were inversely associated with mortality after adjustment for age in both logistic and Cox regression models. Men with final HCT >49.0% (median) suffered lower mortality than men with HCT ≤49.0%. Conclusions: A median HCT increase of 5.0% was associated with TTh, mostly within 48 months of commencing therapy. An increase in HCT (up to 52.0% at final assessment) was independently associated with reduced mortality, indicating current guidelines using a HCT value of 54.0% as a threshold for management change are appropriate until further study.