BACKGROUND: Joint symptoms (eg, arthralgia and arthritis) are a well-known side-effect of aromatase inhibitors. Low oestrogen concentrations and postmenopausal status are associated with the development of these symptoms. Chemotherapy can also induce joint symptoms, but tamoxifen seems to have little effect on their incidence. The aim of this study was to assess the relative importance of different risk factors for treatment-emergent joint symptoms in patients assigned to anastrozole or tamoxifen as adjuvant treatment for postmenopausal breast cancer. METHODS: The Arimidex Tamoxifen Alone or in Combination (ATAC) trial randomly assigned 9366 postmenopausal women to anastrozole (1 mg/day), to tamoxifen (20 mg/day), or to a combination of both. Our analyses were based on data from case reports of 5433 women who were randomly assigned to anastrozole or tamoxifen, who started with their allocated treatment, and who did not have joint symptoms at entry (anastrozole group: n=2698; tamoxifen group: n=2735). The analysis was restricted to the occurrence of joint symptoms at any time during active treatment or within 14 days of its discontinuation. Joint symptoms were defined as any report of arthralgia, arthrosis, arthritis, or joint disorder on a case-report form. Joint disorders were defined as reports of cervical spondylosis, osteoarthritis, and disc herniation. The date of occurrence was recorded, along with a severity score (ie, mild, moderate, or severe). Our analyses were done by use of logistic regression. The ATAC trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. FINDINGS: 777 of 1914 women (40.6%) who used hormone replacement therapy (HRT) before trial entry developed joint symptoms compared with 1001 of 3519 women (28.4%) without previous HRT use (odds ratio [OR] 1.72 [95% CI 1.53-1.93]). Women with hormone-receptor-negative breast cancer developed significantly fewer joint symptoms compared with those with hormone-receptor-positive tumours (124 of 461 [26.9%] vs 1556 of 4548 [34.2%]; OR 0.71 [0.57-0.88]). Women for whom chemotherapy was part of their initial treatment developed significantly more joint symptoms than those who did not receive it (461 of 1219 women [37.8%] vs 1317 of 4214 women [31.3%]; OR 1.34 [1.17-1.53]). Obese women (body-mass index [BMI] >30 kg/m(2)) reported more joint symptoms than women with a BMI of 25-30 kg/m(2) or those with a BMI <25 kg/m(2) (504 of 1354 women [37.2%] vs 502 of 1926 women [31.3%; OR 1.01 (0.88-1.16)] vs 592 of 1908 women [31.0%; OR 1.32 (1.14-1.53)]) and women on anastrozole reported more joint symptoms compared with those on tamoxifen (949 of 2698 women [35.2%] vs 829 of 2735 women [30.3%]; OR 1.25 [1.11-1.40]). All significant risk factors from the univariate analysis were included in a multivariate analysis and remained significant with little change. INTERPRETATION: In this trial, the major risk factors for developing joint symptoms were previous HRT, hormone-receptor positivity, previous chemotherapy, obesity, and treatment with anastrozole. Discussion of identified risk factors is appropriate when counselling women before initiation of adjuvant hormonal treatment. [ABSTRACT FROM AUTHOR]