We studied the association between reproductive factors and bladder cancer incidence in a prospective cohort study of 37,459 Iowa women aged 55-69 years and initially free from cancer in 1986. Women reported reproductive history and were followed prospectively through 2003. After adjusting for age and smoking, there was an inverse association between age at menopause and incident bladder cancer (n 5 192). Compared with menopause at age 48, the hazard ratio (HR) of bladder cancer was 1.32 (95% CI; 0.90-1.94) for menopause at 43-47, and 1.60 (95% CI; 1.06-2.39) for 42 (p-trend 5 0.02). The associations were similar for ages at natural and surgical menopause. In addition, women with a history of bilateral oophorectomy had an increased risk of bladder cancer compared with those who did not undergo bilateral oophorectomy: HR 5 1.58 (95% CI; 1.12, 2.22). Finally, there was an indication of a positive association between bladder cancer and shorter lifetime years of ovulation (p-trend 5 0.09). There were no associations between incident bladder cancer and age at first birth, number of births, age at menarche, use of hormone replacement therapy or any other reproductive characteristics. This study provides evidence that increased risk of bladder cancer is associated with earlier age at menopause in postmenopausal women. ' 2006 Wiley-Liss, Inc.Key words: bladder cancer; postmenopausal women; reproductive factors; age at menopause; prospective study Bladder cancer is one of the most common cancers-61,420 cases are expected to be diagnosed in the United Sates in 2006, 1 constituting about 6% of all new cases among men and 2% of all cases among women.2 Established risk factors for bladder cancers include age, gender, smoking and chemical carcinogens. In most regions of the world, including the United States and northern Europe, bladder cancer is 2.5-4 times more common among men than women. It was shown 3 that in the United States the excessive risk in men persists in the absence of exposure to smoking, occupational hazards or urinary tract infections. Other risk factors, including hormonal and reproductive characteristics, could explain the lower bladder cancer risk in women when compared with men. The hypothesis of a possible association between sex hormones and bladder carcinogenesis is supported by the following facts: estrogen receptors (ERs) are expressed in normal bladder and bladder carcinoma in animal and human models [4][5][6][7][8] ; and estrogen inhibits and testosterone stimulates the growth of bladder tumors in rats. [9][10][11][12] There have been few studies of bladder cancer and reproductive factors. The largest cohort study reported that bladder cancer risk was inversely associated with age at menopause.13 A case-control study found that a greater number of live births was inversely associated with bladder cancer among never-smokers.14 Two case-control studies in Italy 15,16 observed an increased risk of bladder cancer associated with the use of hormone replacement therapy (HRT). Three other studies found ...