Cigarette smoke, a major causative agent of chronic obstructive pulmonary disease (COPD), induces lung cell death by incompletely understood mechanisms. The induction of apoptosis in lung structural cells by cigarette smoke may contribute to the pathogenesis of emphysema. Phosphodiesterase-4 (PDE4) inhibitors are anti-inflammatory agents used in COPD therapy that can prevent cigarette smoke-induced emphysema in mice. We investigated the effect of rolipram, a first generation PDE4 inhibitor, on the regulation of cigarette smoke-induced apoptosis. Human lung fibroblast (MRC-5) cells were exposed to cigarette smoke extract (CSE). Cell viability and apoptosis were determined by MTT assay and Annexin-V staining, respectively. Caspase activation was determined by Western immunoblot analysis. Rolipram protected against cell death and increased viability in MRC-5 fibroblasts after CSE exposure. Furthermore, rolipram protected against apoptosis, decreased caspase-3 and -8 cleavage in MRC-5 cells exposed to CSE. Pre-treatment with rolipram enhanced Akt phosphorylation and associated cytoprotection in CSE-treated cells, which could be reversed by the PI3K inhibitor LY294002 partly. In conclusion, rolipram protects against apoptosis of MRC-5 cells through inhibition of caspase-3 and caspase-8. Rolipram may represent an effective therapeutic agent to reduce cigarette smoke-induced apoptosis of lung fibroblasts.