Background: Small cell lung cancer (SCLC) is an aggressive cancer often presenting in an advanced stage and prognosis is poor. Early response evaluation may have impact on the treatment strategy. Aim: We evaluated ¹⁸F-fluorothymidine-(FLT)-PET/diffusion-weighted-(DW)-MRI early after treatment start to describe biological changes during therapy, the potential of early response evaluation, and the added value of FLT-PET/DW-MRI. Methods: Patients with SCLC referred for standard chemotherapy were eligible. FLT-PET/DW-MRI of the chest and brain was acquired within 14 days after treatment start. FLT-PET/DW-MRI was compared with pretreatment FDG-PET/CT. Standardized uptake value (SUV), apparent diffusion coefficient (ADC), and functional tumor volumes were measured. FDG-SUV_peak, FLT-SUV_peak, and ADC_median; spatial distribution of aggressive areas; and voxel-by-voxel analyses were evaluated to compare the biological information derived from the three functional imaging modalities. FDG-SUV_peak, FLT-SUV_peak, and ADC_median were also analyzed for ability to predict final treatment response. Results: Twelve patients with SCLC completed FLT-PET/MRI 1–9 days after treatment start. In nine patients, pretreatment FDG-PET/CT was available for comparison. A total of 16 T-sites and 12 N-sites were identified. No brain metastases were detected. FDG-SUV_peak was 2.0–22.7 in T-sites and 5.5–17.3 in N-sites. FLT-SUV_peak was 0.6–11.5 in T-sites and 1.2–2.4 in N-sites. ADC_median was 0.76–1.74 × 10^{− 3} mm²/s in T-sites and 0.88–2.09 × 10⁻³ mm²/s in N-sites. FLT-SUV_peak correlated with FDG-SUV_peak, and voxel-by-voxel correlation was positive, though the hottest regions were dissimilarly distributed in FLT-PET compared to FDG-PET. FLT-SUV_peak was not correlated with ADC_median, and voxel-by-voxel analyses and spatial distribution of aggressive areas varied with no systematic relation. LT-SUV_peak was significantly lower in responding lesions than non-responding lesions (mean FLT-SUV_peak in T-sites: 1.5 vs. 5.7; p = 0.007, mean FLT-SUV_peak in N-sites: 1.6 vs. 2.2; p = 0.013). Conclusions: FLT-PET and DW-MRI performed early after treatment start may add biological information in patients with SCLC. Proliferation early after treatment start measured by FLT-PET is a promising predictor for final treatment response that warrants further investigation. Trial registration: Clinicaltrials.gov, NCT02995902. Registered 11 December 2014 - Retrospectively registered.