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Photodynamic therapy (PDT) is an established nonsurgical treatment for nodular basal cell carcinoma (nBCC). This study compares the clinical, histopathological, and immunohistochemical findings in recurrent nBCC after PDT versus pre-treatment (primary) nBCC. This retrospective study analyzed nodular BCCs treated with methyl aminolevulinate (MAL)-PDT at the Department of Dermatology, San Jorge Hospital (Huesca, Spain), between 2006 and 2015. Only cases in which both the primary and the recurring tumor were histologically confirmed were included in the analysis. Data on clinical, histological, and immunohistochemical variables were collected. The analysis included a total of 15 nBCCs resistant to 2 sessions of MAL-PDT: 11 (73.3%) were persistent BCCs (cure not achieved within 3 months of treatment) and 4 (26.7%) recurred in the first 2 years of follow-up. Subsequent biopsies of the 11 persistent nBCCs revealed that 9 (81.8%) retained the same histological type while the other 2 (18.2%) had another histological variant (micronodular and metatypical). Biopsy of the 4 recurring nBCCs revealed a persistent nodular subtype in all cases. MAL-PDT resulted in no changes in p53, survivin or β-catenin expression, and trend toward increased EGFR immunostaining. Histology revealed a trend toward a dense stroma without ulceration in recurrent nBCC after PDT. Trend toward increased EGFR immunostaining, and no changes in survivin (which remained negative or mildly positive) or β-catenin, (which remained moderately or our findings indicate that MAL-PDT does not induce histological or immunohistochemical changes that increase tumor aggressiveness.