Abstract Background Cigarette smoking, adiposity, unhealthy diet, heavy alcohol drinking and physical inactivity together are associated with about half of premature deaths in Western populations. The aim of this study was to estimate their individual and combined impacts on residual life expectancy (RLE). Methods Lifestyle and mortality data from the EPIC-Heidelberg cohort, comprising 22,469 German adults ≥40 years and free of diabetes, cardiovascular disease and cancer at recruitment (1994–1998), were analyzed with multivariable Gompertz proportional hazards models to predict lifetime survival probabilities given specific baseline status of lifestyle risk factors. The life table method was then used to estimate the RLEs. Results For 40-year-old adults, the most significant loss of RLE was associated with smoking (9.4 [95% confidence interval: 8.3, 10.6] years for male and 7.3 [6.0, 8.9] years for female heavy smokers [>10 cigarettes/day]; 5.3 [3.6, 7.1] years for men and 5.0 [3.2, 6.6] years for women smoking ≤10 cigarettes/day). Other lifestyle risk factors associated with major losses of RLE were low body mass index (BMI 4 drinks/day, 3.1 [1.9, 4.0] years for men), and high processed/red meat consumption (≥120 g/day, 2.4 [1.0, 3.9] years for women). The obesity-associated loss of RLE was stronger in male never smokers, while the loss of RLE associated with low BMI was stronger in current smokers. The loss of RLE associated with low leisure time physical activity was moderate for women (1.1 [0.05, 2.1] years) and negligible for men (0.4 [−0.3, 1.2] years). The combined loss of RLE for heavy smoking, obesity, heavy alcohol drinking and high processed/red meat consumption, versus never smoking, optimal BMI (22.5 to 24.9), no/light alcohol drinking and low processed/red meat consumption, was 17.0 years for men and 13.9 years for women. Conclusions Promoting healthy lifestyles, particularly no cigarette smoking and maintaining healthy body weight, should be the core component of public health approaches to reducing premature deaths in Germany and similar affluent societies.