<p>Squamous cell carcinoma of the lung with an acantholytic pseudoglandular pattern of growth is a rare presentation of pulmonary squamous cell carcinoma that can pose difficulties for diagnosis. We have studied 14 lung tumors showing striking pseudoglandular features that led to confusion with adenocarcinoma or adenosquamous carcinoma. The patients were six women, and eight men aged 64–88&#xa0;years (median = 74.5&#xa0;years). The tumors measured from 1.4 to 8.5&#xa0;cm (mean = 4.6&#xa0;cm); five cases were peripherally located and nine were hilar. The tumors were characterized by squamous cell carcinoma histology with admixed pseudoglandular areas composed of irregular islands of large round to polygonal tumor cells with abundant cytoplasm and closely apposed cell borders that showed central gland-like or tubular spaces lined by atypical cells; in many cases, tumor cells could be seen projecting into the lumen displaying an acantholytic pattern with dyskeratosis. Immunohistochemical stains showed nuclear positivity of the tumor cells for p40 and CK5/6, and negative staining for napsin-A and TTF1. Next-generation sequencing was performed in 12 cases and showed point mutations in 8/12 (66%) of patients, most commonly involving the <i>TP53</i> gene, and copy number variations in 4/12 (33%) of cases, involving 11 different genes. Seven patients died of tumor between 3&#xa0;months and 7&#xa0;years (median = 4.0&#xa0;years); three patients were alive and free of disease from 4 to 5&#xa0;years, and 1 patient was alive with tumor at 4&#xa0;years and then lost to follow-up. Squamous cell carcinoma of lung with acantholytic and pseudoglandular features is an unusual histologic presentation of lung squamous cell carcinoma that can cause diagnostic difficulties; awareness of this presentation and application of immunohistochemical stains is of importance for correct diagnosis.</p>