Background Small cell lung cancer (SCLC) is a chemotherapy-responsive tumor type but most patients ultimately experience disease progression. SCLC is associated with alterations in the coagulation system. The present randomized clinical trial (RCT) was designed to determine whether addition of low-molecular-weight heparin (LMWH) to combination chemotherapy (CT) would improve SCLC outcome compared with CT alone. Methods Combination CT consisted of cyclophosphamide, epirubicine and vincristine (CEV) given at 3-weekly intervals for six cycles. Eighty-four patients were randomized to receive either CT alone (n=42) or CT plus LMWH (n=42). LMWH consisted of dalteparin given at a dose of 5000 U once daily during the 18 weeks of CT. Results Overall tumor response rates were 42.5% with CT alone and 69.2% with CT plus LMWH (P=0.07). Median progression-free survival was 6.0 months with CT alone and 10.0 months with CT plus LMWH (P=0.01). Median overall survival was 8.0 months with CT alone and 13.0 months with CT plus LMWH (P=0.01). Similar improvement in survival with LMWH treatment occurred in patients with both limited and extensive disease stages. The risk of death in the CT+LMWH group relative to that in the CT group was 0.56 (95% confidence interval 0.30, 0.86) (P=0.012 by log rank test). Toxicity from the experimental treatment was minimal and there were no treatment-related deaths. Conclusions These results support the concept that anticoagulants, and particularly LMWH, may improve clinical outcomes in SCLC. Further clinical trials of this relatively non-toxic treatment approach are indicated.