Circulating tumor cells (CTCs) may provide a liquid biopsy approach to disease monitoring in small cell lung cancer (SCLC), a particularly aggressive tumor subtype. Yet, the prognostic role of CTCs during and after treatment in relation to baseline remains ill-defined. Here, we assessed the value of longitudinal CTC analysis and the potential of low-molecular-weight heparin (LMWH) to reduce CTC abundance in SCLC patients from a randomized trial (RASTEN). Blood samples were collected at baseline, before chemotherapy Cycle 3, and at 2-month follow-up from 42 patients in total, and CTCs were quantified using the FDA-approved CellSearch system. We found a gradual decline in CTC count during and after treatment, independently of the addition of LMWH to standard therapy. Detectable CTCs at baseline correlated significantly to reduced survival compared to undetectable CTCs (unadjusted hazard ratio (HR) of 2.75 (95% CI 1.05–7.20; p = 0.040)). Furthermore, a persistent CTC count at 2-month follow-up was associated with a HR of 4.22 (95% CI 1.20–14.91; p = 0.025). Our findings indicate that persistently detectable CTCs during and after completion of therapy offer further prognostic information in addition to baseline CTC, suggesting a role for CTC in the individualized management of SCLC.