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The internal target volume (ITV) strategy generates larger planning target volumes (PTVs) in locally advanced non-small cell lung cancer (LA-NSCLC) than the Mid-position (Mid-p) strategy. We investigated the benefit of the Mid-p strategy regarding PTV reduction and dose to the organs at risk (OARs). 44 patients with LA-NSCLC were included in a randomized clinical study to compare ITV and Mid-p strategies. GTV were delineated by a physician on maximum intensity projection images and on Mid-p images from four-dimensional CTs. CTVs were obtained by adding 6 mm uniform margin for microscopic extension. CTV to PTV margins were calculated using the van Herk's recipe for setup and delineation errors. For the Mid-p strategy, the mean target motion amplitude was added as a random error. For both strategies, three-dimensional conformal plans delivering 60–66 Gy to PTV were performed. PTVs, dose–volume parameters for OARs (lung, esophagus, heart, spinal cord) were reported and compared. With the Mid-p strategy, the median of volume reduction was 23.5 cm3 (p = 0.012) and 8.8 cm3 (p = 0.0083) for PTVT and PTVN respectively; the median mean lung dose reduction was 0.51 Gy (p = 0.0057). For 37.1% of the patients, delineation errors led to smaller PTV with the ITV strategy than with the Mid-p strategy. PTV and mean lung dose were significantly reduced using the Mid-p strategy. Delineation uncertainty can unfavorably impact the advantage. To the best of our knowledge, this is the first dosimetric comparison study between ITV and Mid-p strategies for LA-NSCLC. [ABSTRACT FROM AUTHOR]