Dirofilaria repens is the primary etiological agent of human dirofilariosis in the Old World, with Italy reporting the highest number of cases in Europe. This study describes two new cases of D. repens infection in humans, in southern Italy, where canine dirofilariosis is endemic. The first case involved a 33-year-old man from Caserta (Campania, Southern Italy) who presented with a subcutaneous mass on the upper eyelid. Surgical excision revealed an immature female D. repens worm measuring 14 cm, lacking microfilariae in both the uterus and peripheral blood. The second case was a 67-year-old man from Pozzuoli (Metropolitan City of Naples, Southern Italy) with an oval-shaped nodule in the left frontal scalp region. A live gravid female D. repens worm measuring 15–16 cm was extracted, also without microfilariae in the peripheral blood and no male worm detected. PCR sequencing confirmed a 100% match with D. repens. Both patients tested positive for D. repens antibodies by IgG ELISA. These cases underscore the continuous spread of human dirofilariosis in southern Italy and highlight diagnostic challenges due to variable clinical presentations. The discovery of a gravid female without microfilaremia suggests complexities in the parasite’s life cycle in humans, challenging the notion of humans as strict dead-end hosts. Given the rising prevalence in both humans and dogs, a comprehensive epidemiological study is recommended. Inclusion of dirofilariosis in the national surveillance system for notifiable diseases would improve case identification and tracking, aiding in better monitoring and control of this zoonotic infection.