The aim of this work was to reveal potential joint effects of the risk factors subjective cognitive decline (SCD) and apolipoprotein E (APOE) ɛ4 genotype on incident mild cognitive impairment (MCI) in men and women separately. Six hundred and five men and 593 women of the general population were grouped according to their presence or absence of SCD and APOE ɛ4 genotype and examined separately. Groups were compared regarding their sociodemographic characteristics and their objective cognitive performance. Risk of incident MCI was analyzed with logistic regression models. APOE ɛ4-negative men and women without SCD served as the reference group. Potential interaction effects of SCD and APOE ɛ4 genotype on incident MCI were estimated. Participants in the different SCD and APOE ɛ4 genotype groups showed very subtle differences regarding their cognitive performance. It could be shown for the first time that two risk factors for cognitive decline, SCD in objectively normal individuals and APOE ɛ4, have a differential interaction effect on incident MCI and that this association is dependent on sex. The highest risk for incident MCI after 5 years was observed for APOE ɛ4-negative men with SCD (single-risk group), approximately 2.5-fold increased, and for APOE ɛ4-positive women with SCD (high-risk group), approximately 3.5-fold increased, compared with individuals without the two risk factors. This suggests that SCD in cognitively healthy individuals of the general population may have a different impact as a predictor of incident MCI in men and women as well as APOE ɛ4 carriers and non-carriers. It should thus be examined and interpreted with regard to these differences. The selected study sample of the longitudinal Heinz Nixdorf Recall study is representative of the older, general population in an optimal age range to investigate preclinical and prodromal Alzheimer’s disease (AD) stages. This work highlights the need to further characterize SCD as a complex, interconnected construct or symptom. Its optimal assessment remains to be established.