Objective This study aimed to investigate the importance of combined psychosocial work factors for the risk of long-term sickness absence (LTSA). Methods We followed 69 371 employees in the general working population (Work Environment and Health in Denmark study 2012–2018), without LTSA during the preceding year, for up to two years in the Danish Register for Evaluation of Marginalization. Using k-means cluster analyses and weighted Cox-regression controlling for age, gender, survey year, education, health-behaviors, and physical work demands, we determined the prospective association of 11 identified clusters – based on the combination of nine psychosocial work factors (recogni-tion, quantitative demands, work pace, emotional demands, influence, justice, role clarity, role conflicts, and support from colleagues) – with the risk of LTSA. Results During 124 045 person-years of follow-up, 6197 employees developed LTSA (weighted 8.5%). Using the cluster with the most favorable psychosocial scores as reference, clusters scoring poorly on several combined psychosocial factors had increased risk of LTSA. The cluster scoring poor on all nine psychosocial factors exhibited the highest risk [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.45–1.94]. Scoring poorly on one or two psychosocial factors did not increase the risk of LTSA when combined with favorable scores on the other psychosocial factors. Interaction analyses showed that gender, but not age and education, modified the association between cluster and LTSA. Conclusion Scoring poorly on several combined psychosocial work factors plays an important role in the risk of LTSA. Scoring favorably on several psychosocial factors outweighed the potentially adverse effects of scoring poorly on one or two factors.