Objective To investigate the clinical significance of CT scan and the detection of expression levels of synaptophysin (Syn) and chromogranin (CgA) in cancer tissues of patients with small cell lung cancer (SCLC). Methods Forty-five patients with SCLC and fifty patients with non-small cell lung cancer (NSCLC) pathologically confirmed in the hospital from March 2015 to March 2017 were selected. All patients underwent CT examination before operation. The expression of neuroendocrine markers Syn and CgA in cancer tissues and adjacent tissues was detected by immunohistochemistry. Results The incidence rates of CT signs pleural effusion and mediastinal lymph node fusion in SCLC group (44.44% and 71.11%) were significantly higher than those in NSCLC group (20.00% and 16.00%) (P<0.05). However, there was no significant difference between the two groups in the other CT signs such as pericardial effusion, pleural metastasis, distant metastasis and macrovascular invasion (P>0.05). The positive expression rates of Syn and CgA in SCLC group (86.67% and 53.33%) were significantly higher than those in NSCLC group (16.00% and 4.00%) (P<0.05). The sensitivity, specificity and accuracy of CT combined with Syn and CgA in the diagnosis of SCLC (93.33%, 94.00% and 93.68%) were significantly better than those of single test (P<0.05). Conclusion The expression of Syn and CgA in SCLC and NSCLC are significantly different. Combined use of CT scan can help to improve the differential diagnosis of SCLC.