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Abstract Gender specific all-cause mortality risk associated with a high somatic symptom burden (SSB) in a population-based cohort was investigated. The study population included 5679 women and 5861 men aged 25–74 years from the population-based MONICA/KORA Cohort. SSB was assessed following the Somatic Symptom Scale-8 and categorized as very high (≥ 95th percentile), high (60–95th percentile), moderate (30–60th percentile), and low (≤ 30th percentile). The impact of SSB on all-cause mortality risk within a mean follow-up period of 22.6 years (SD 7.1; 267,278 person years) was estimated by gender-specific Cox regression models adjusted for sociodemographic, lifestyle, somatic and psychosocial risk factors, as well as pre-existing medical conditions. Approximately 5.7% of men and 7.3% of women had very high SSB. During follow-up, 3638 (30.6%) mortality cases were observed. Men with a very-high SSB had 48% increased relative risk of mortality in comparison to men with a low SSB after adjustment for concurrent risk factors (1.48, 95% CI 1.20–1.81, p < .0001), corresponding to 2% increased risk of mortality for each 1-point increment in SSB (1.02; 95% CI 1.01–1.03; p = 0.03). In contrast, women with a very high SSB had a 22% lower risk of mortality (0.78, 95% CI 0.61–1.00, p = 0.05) and women with high SSB had an 18% lower risk of mortality (0.82; 95% CI 0.68–0.98, p = 0.03) following adjustment for concurrent risk factors. The current findings indicate that an increasing SSB is an independent risk factor for mortality in men but not in women, pointing in the direction of critical gender differences in the management of SSB, including women’s earlier health care utilization than men.