BACKGROUND: We report an open spontaneous anecdotical retrospective survey of Corynebacterium parvum administration to 4000 fragile immune-depressed and multimorbid patients treated with a killed C. parvum strain to enhance the innate immunity integrating the adaptative immune response for a long-standing antinfectious resistance. METHODS: Four thousand patients (1900 men and 2100 women) with mild, moderate or chronic disease, appealing to our Second Opinion Medical Consultation Network, signed an informed consent and were injected with C. parvum. The treatment was followed-up at 6 months after therapy, filling the short form of the medical outcome health survey questionnaire (SF-36), directly by the patients or its relatives and monitoring the health regularly via telemedicine (Skype, WhatsApp, mail, etc.) or physician's visit. RESULTS: The main efficacy endpoints, as assessed by the SF-36 Questionnaire, are significant improvements in the mental and physical role functioning score (P<0.02), in general health, in social role functioning (P<0.02), vitality (P<0.03), and a significant reduction in bodily pain (P<0.03). There was a significant improvement or complete regression of the herpetic eruptions observed in 1000 affected patients and of herpetic neuralgia (reduced in 80% of cases), also full recovery or frequency reduction (30%) of recurrent cystitis and prostatitis in 120 affected patients, and last, but not least, a life quality improvement in 100 oncologic patients of overall 200 cases. A significant increase in the lymphocyte count (P<0.0001), mainly Helper lymphocytes. CONCLUSIONS: Even if our study cannot be enclosed into the evidence-based medicine parameters, our results due to the relevant patient's sample size are worth to be considered in order to plan more qualified clinical investigations.