Background: Starting a study programme at an university, students are confronted with rising requirements regulating their learning processes and motivation. Both difficulties due to this regulation and the quality of instruction are associated with students dropping out from a study programme in the research. Aims: The purpose of this research is to analyse the interplay and effect of difficulties in self-regulated learning, achievement motivation (i.e. academic self-concept, subject interest), and perceived quality of instruction in dropping out from an university study programme. Sample: We sampled 2301 cooperative students in their first academic year. The average age was M = 22.12 (SD = 3.02), and 1167 were male (50.7%). Method: This cross-sectional study used structural equation models for hypothesis analysis. Three years after the survey, dropout information from the university administration was matched to the survey data. Results: The results indicate associations between academic self-concept, subject interest and difficulties in regulating one's motivation with dropout. An indirect effect was found between perceived quality of instruction and dropout via academic self-concept, subject interest and difficulties in regulating one's motivation. Conclusions: The relevance of perceived quality of instruction, self-concept, subject interest and difficulties in motivational regulation and consequences for dropout is illustrated.