Aims: To compare serum protein expression profiles between lung cancer patients and healthy individuals, and to examine whether there are differences in serum protein expression profiles among patients with lung cancers of different histological types and whether the characteristic expression of serum proteins may assist in differential diagnosis of various subtypes of lung cancers. Methods: Blood samples were collected from 123 lung cancer patients before commencement of treatment who attended Shanxi Cancer Hospital, China, between 2008 and 2013. Blood samples from 60 healthy individuals were also collected in the same period. Serum protein expression profiles were analyzed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. The differences in the serum protein spectrums of lung cancer patients with different histological subtypes were analyzed by one-way Analysis of Variance and receiver operating characteristic curves. Results: A cluster of 48 protein mass-to-change ratio (M/Z) peaks was differentially expressed between sera of lung cancer patients and healthy individuals. The M/Z 1205, 4673, 1429 and 4279 peaks were differentially expressed among patients with lung squamous cell carcinomas, adenocarcinomas and small-cell lung carcinomas. Conclusion: These results reinforce the notion that profiling of serum proteins may be of diagnostic value in lung cancer, and suggest that the differences in serum protein profiles may be useful in differential diagnosis of lung cancers of varying histological subtypes.