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Introduction Loneliness has social and health implications. The aim of this article is to evaluate the association of loneliness with all-cause mortality. Methods Pubmed, PsycINFO, CINAHL and Scopus databases were searched through June 2016 for published articles that measured loneliness and mortality. The main characteristics and the effect size values of each article were extracted. Moreover, an evaluation of the quality of the articles included was also carried out. A meta-analysis was performed firstly with all the included articles and secondly separating by gender, using a random effects model. Results A total of 35 articles involving 77220 participants were included in the systematic review. Loneliness is a risk factor for all-cause mortality [pooled HR = 1.22, 95% CI = (1.10, 1.35), p < 0.001] for both genders together, and for women [pooled HR = 1.26, 95% CI = (1.07, 1.48); p = 0.005] and men [pooled HR = 1.44; 95% CI = (1.19, 1.76); p < 0.001] separately. Conclusions Loneliness shows a harmful effect for all-cause mortality and this effect is slightly stronger in men than in women. Moreover, the impact of loneliness was independent from the quality evaluation of each article and the effect of depression.