Objective: We aimed to evaluate which risk factors in middle-aged women are associated with higher risk of multimorbidity in older age. Study design: We conducted a prospective cohort study from 1990 to 1993 in Santiago de Chile, Chile among women aged 40–59 (at baseline). Diagnosed illnesses were retrieved from national health records in 2020. Main outcome measures: : Clinical and laboratory evaluation was conducted. Results: 1066 women were followed-up for a mean of 27.8 years, after which 49.7% presented multimorbidity. These women, as compared with those without multimorbidity, were more likely at baseline to have had obesity (20.4% vs. 8.6%, p < 0.001); be post-menopause (47.2% vs. 40.5%; p < 0.03); have jobs that did not require a qualification (74.2% vs. 56.0%, p < 0.001); arterial hypertension (19.8% vs 14.4%, p < 0.018); lower HDL-cholesterol (51.3 ± 12.9 vs. 53.6±12.7 mg/dL, p < 0.005); and higher triglyceride levels (136.0 ± 65.0 vs. 127.0 ± 74.0 mg/dL, p = 0.028). Hypertension was associated in 22.0% of women with diabetes, in 20.9% with osteoarthritis and 14.0% with depression. Osteoarthritis was also associated with diabetes mellitus (8.3%) and depression (7.8%). Diabetes mellitus, in addition to hypertension and osteoarthritis, was associated with depression (6.4%). In a logistic regression model, we observed that obesity in middle-aged women was the strongest risk factor for multimorbidity in the elderly (OR: 2.48; 95% CI, 1.71–3.61), followed by having a job that did not require a qualification (OR: 2.18; 95% CI, 1.67–2.83) and having a low HDL-cholesterol level (OR: 1.31; 95% CI, 1.02–1.68). Conclusions: Multimorbidity was highly prevalent in this older female population. Obesity in middle-aged women was the strongest risk factor for multimorbidity at older age. These results are relevant for Chile and other countries with similar population profiles.