Reactive oxygen species (ROS) have been implicated in skin tumor promotion. Earlier, we showed that porphyrin-mediated cutaneous photosensitization results in the in situ generation of ROS. Recently, we have provided the first in situ evidence for the involvement of ROS in stage I tumor promotion. In this study we further show that in situ-generated ROS act as weak complete tumor promoters in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. Papillomas were induced in Swiss albino mice by a single topical application of DMBA as initiator. The promotion was achieved in these mice by the sustained generation of ROS through dihematoporphyrin ether (DHE)-mediated cutaneous photosensitization, which was done once every day (six times a week) for 24 weeks. The first appearance of visible papillomas could be recorded 24 weeks after the initiation. The highest tumor incidence of 60% occurred at a dose of 2.5 mg/kg body wt DHE. Increasing the dose of DHE produced a decrease in the incidence as well as in the number of papillomas. In contrast, the number of carcinomas/mouse increased with increasing dose of DHE. Histopathology of the tumor samples indicated the formation of in situ carcinoma also in skin. ROS generated through DHE-mediated photosensitization resulted in a ~3 fold induction of ODC activity 9 h after photosensitization. DHE-mediated photosensitization enhanced [3H]thymidine incorporation in cutaneous DNA in a dose-dependent manner. A maximum 5-fold induction of [3H]thymidine incorporation was observed at a dose of 10 mg/kg body wt DHE. The longer latency period, low incidence of tumor induction, low tumor yield and low induction of ODC activity as compared with TPA represent the weak but, complete tumor promoting potential of in situ-generated ROS. The low tumor incidence and tumor yield observed at higher doses of DHE may be due to the ablation of tumors at early stages due to the strong photodynamic action of DHE. Our data indicate that porphyrin-mediated photosensitization has a weak tumor promoting effect in mouse skin and in situ-generated ROS may play an important role in the development of this response.