Objective: To evaluate the association between premature ovarian insufficiency (POI) and mortality. Materials and methods: This was a secondary analysis of a long-term cohort of Chilean women who received preventive health care between 1990 and 1993. The exposure variable was POI and the outcome was death, and follow-up time was 30 years. Patient data were extracted from medical records. Data related to deaths were obtained from the records of the official government registry as of January 2021. Cox regression proportional hazard models were used to estimate crude and adjusted hazard ratios (HR) and 95 % confidence intervals (CI). Results: Data for a total of 1119 women were included in the analysis. Median age was 47 years (interquartile range: 44–52). The baseline prevalence of POI was 6.7 %. At the end of the follow-up, 34.7 % of women with POI had died, compared with 19.3 % of women without the condition (p < 0.001). A larger proportion of women with POI died from cardiovascular disease (12.0 % vs. 5.1 %; OR: 2.55, 95 % CI: 1.21–5.39) whereas there was no significant difference in cancer mortality (6.7 % vs. 7.7 %; OR: 0.86, 95 % CI: 0.34–2.19). In the adjusted Cox model, POI was among the main factors associated with mortality (hazard ratio [HR] 1.60, 95 % CI: 1.03–2.47), after diabetes (HR 2.51, 95 % CI: 1.40–4.51) and arterial hypertension (HR 1.75, 95 % CI: 1.29–2.37). Conclusion: Although POI affects a small group of women, its association with mortality seems to be relevant; hence it is necessary to implement measures that reduce this risk.