Photodynamic therapy (PDT) is an important noninvasive strategy of treatment for selected cases of basal cell carcinoma (BCC), the commonest malignancy in humans. The efficacy of PDT in the treatment of nodular BCC (BCCn) is not established, with cure and recurrence rates highly variable. The improvement of photosensitizing agents in terms of specificity, potency and skin penetration is an important perspective for achieving better results with PDT. In this regard, Nanotechnology and its potential in improving drug releasing systems are very promising. In this study, the efficacy and side effects of two photosensitizing precursors in the treatment of BBCnup to 2 mm deep were investigated, the aminolevulinic acid in polymeric lipid nanoemulsion, the Nano-ALA, and methylaminolevulinate, the M-ALA. The study included 24 patients with a total of 30 BCCn lesions, randomly divided into two treatment groups. Two standard PDT sessions were performed one week apart and three months later the treated area underwent surgical excision. 26 lesions (86.7%) were located in the face and 16 (53.3%) were at high risk area. In total, the histological cure rate was 50% and there was no significant difference between the two groups (M-ALA = 62.5% and Nano-ALA = 35.7%; P = 0.14). Some factors may have impaired Nano-ALA results, such as a greater number of lesions at high risk areas and the presence of different types and subtypes of BCCn in this group. The treatment was overall well tolerated, with pain scores, erythema and edema similar in both groups. The only poor response predictor was the location of the tumor in high-risk areas. In conclusion, the performance of Nano-ALA in terms of efficacy and tolerability was similar to that of M-ALAin PDT for BCCn. The relatively low cure rate in this study suggests that PDT in the treatment of CBCn should be indicated in selected cases and used with caution.