Background: Drinking and smoking have economic consequences and are the main risk factors of mortality and morbidity. Disease-specific deaths attributable to using substances present the primary health indicator in this study. This analysis focuses on mortality in productive age, 15 to 64 years since those deaths are considered the highest economic burden. Method: In the analytical part, data from the Registry of deaths of the Czech Republic for 1994 to 2017 were used. The number of deaths attributable to smoking and drinking was calculated using attributable fractions, based on literature review. This research aimed to reveal the gender differences in deaths attributable to drinking and smoking, according to age, and the differences in deaths regarding smoking or drinking. Results: The mortality attributable to smoking and drinking differs across age groups and genders. The highest median share of tobacco-related deaths is in the age group, 60—64 years. The highest median share of alcoholic deaths is in the age group of 50—54 years. Conclusions: There are significant differences between genders in both, smoking and drinking. A prevention program should be targeted to different age groups.