To determine whether the fertility quality of life differs between infertile couples from urban and rural areas in China. A cross-sectional prospective study consisting of 670 infertile couples in assisted reproduction clinic of the First Affiliated Hospital of Zhengzhou University was conducted. Among all participants, 358 infertile couples (31.22 years for women and 32.58 years for men) were urban residents and 312 (29.79 years for women and 30.77 for men) were from rural areas. Male and female counterparts completed the FertiQoL questionnaire independently. Paired t-test was utilized to explore the differences of fertility quality of life (QoL) between urban and rural infertile couples. Whether and to what extent various characteristics contribute to the differences regarding fertility QoL was assessed by multiple stepwise regression analysis. For all patients, women obtained significantly lower FertiQoL questionnaire scores compared with male counterparts, indicating lower fertility quality of life. Infertile couples resided in rural areas had considerably lower FertiQoL scores than those from urban residents. Coping style, cognition of children, family monthly net income, employment status, educational level and social support were risk factors predicting the differences in the fertility quality of life between urban and rural infertile couples. The results show the fertility QoL significantly differs between infertile couples from urban and rural areas. According to different characteristics of coping style, cognition of children, family monthly net income, employment status, educational level and social support, targeted measures should be taken to resolve the difference, especially for rural women.