Background: Most cancer survivors are able to return to work at some point after diagnosis. However, literature on sustained employability and health-related quality of life (HRQoL) is limited. Therefore, the aims of this study were to explore the influence of change in employment status on HRQoL in cancer survivors long term after diagnosis, and to identify predictors of work continuation in occupationally active survivors. Material and methods: We used prospective data (T0 = two years after diagnosis, T1 = one-year follow-up, and T2 = two-year follow-up) from a cohort of cancer survivors that had an employment contract and were of working age at T0 (N = 252, 69.8% female). Groups were formed on the basis of change in employment status: ‘continuously not working’ (19.8%), ‘positive change in employment status’ (5.6%), ‘negative change in employment status’ (14.7%), and ‘continuously working’ (59.9%). ANCOVA was used to explore the relationship between change in employment status and HRQoL at T1. Generalized estimating equations (GEE) were used to identify predictors of work continuation (at T1 and T2) in survivors that were occupationally active at T0 (N = 212). Results: ‘Continuously working’ survivors scored significantly better on the EORTC QLQ-C30 scales: role functioning, fatigue, pain, constipation, global health/QoL and the Summary score, than ‘continuously not working’ survivors, and better on physical, role and emotional functioning, fatigue, financial impact, global health/QoL and the Summary score than survivors with a ‘negative change in employment status’ (effect size range = 0.49–0.74). In occupationally active survivors, a high score on current work ability was associated with work continuation one year later [odds ratio (OR) 1.46; 95% CI 1.11–1.92]. Conclusion: Cancer survivors ‘continuously working’ function better and have a better health and QoL than those who are not able to work. However, in occupationally active cancer survivors, one should monitor those with low self-perceived work ability, because they have an increased risk to discontinue their work.