BACKGROUND: Cumulative IVF pregnancy rates are compromised by the large number of couples who drop-out of treatment before achieving pregnancy. The aim of this study was to identify the role of the treatment strategy applied, and potential other factors that influence the decision of couples to discontinue treatment. METHODS: The incidence of drop-out from IVF treatment and factors related to drop-out were studied in a cohort of IVF patients aged <38 years embarking on IVF treatment either with a mild or a standard treatment strategy for a planned maximum number of treatment cycles. RESULTS: Of the 384 couples studied, 17% dropped out of IVF treatment. The physical or psychological burden of treatment was the most frequent cause of drop-out (28%). The application of a mild treatment strategy (mild ovarian stimulation along with the transfer of a single embryo) significantly reduced the chance of drop-out (hazard ratio (HR) 0.55; 95% confidence interval (CI), 0.31-0.96). When a mild IVF strategy was employed, the association between the baseline anxiety score and drop-out was reduced by >50%. The presence of severe male subfertility (HR 4.80; 95% CI, 1.63-14.13) and the failure to achieve embryo transfer (odds ratio 0.41; 95% CI, 0.24-0.72) were also related to drop-out. CONCLUSIONS: Reducing drop-out rate is crucial to further improve the efficacy and cost-effectiveness of IVF treatment. An important factor determining the risk of drop-out is the burden of the treatment strategy. The application of a mild treatment strategy and managing patient's expectations might reduce drop-out rates.