This study explores individual and contextual risk factors in relation to work interfering with private life (WIL) and private life interfering with work (LIW) among self-employed men and women across European countries. It also studies the relationship between interference (LIW and WIL) and well-being among self-employed men and women. Drawing on data from the fifth round of the European Working Conditions Survey, a sample of self-employed men and women with active businesses was extracted. After applying multilevel regressions, results show that although business characteristics are important, the most evident risk factor for WIL and LIW is time demands. Both time demands and business characteristics also seem to be important factors in relation to gender differences in level of interference. There is a relationship between well-being and both WIL and LIW, and time demands is again an important factor. Gender equality in the labor market did not relate to level of interference, nor did it affect the relationship between interference and well-being. However, in gender-separated analyses, LIW and LIW interacted with gender equality in the labor market in different ways for women’s and men’s well-being. In conclusion, gender relations are important in interference and how interference relates to well-being.