Background: Sexually transmitted infections (STIs), particularly genital ulcer diseases (GUD) are a neglected field in health care, partly due to the stigma associated with the diseases. Coinfection with HIV alters the clinical presentation, natural history and response to treatment. Moreover, STIs contribute significantly to increased risk of HIV transmission. Management of STIs at primary health care level is syndromic, driven by algorithms. In the absence of interest and expertise at secondary/tertiary care centres patients, who fail this management, suffer. Methods &Materials: We present a retrospective chart review of patients referred to our a specialist Infectious Diseases Unit with challenging or unusual STI/GUD,who did not respond to syndromic management. Results: We have closely documented 42 patients (23 male, 39 HIV positive) seen at King Edward VIII hospital for STI/GUD. The patients had an average of 2.6 different primary health care providers (range: 1-5) before coming to the tertiary site. Only 54.8% were formally referred. 15patientshadextensive chronicHSVulcers (8males, allHIV+ ). Of these, 7 responded to high doses of acyclovir (400mg 8 hourly to 800mg 5 times daily). Duration of treatment varied from 7 to 21 days. 6 chronic HSV ulcers (4 males) failed high dose acyclovir but responded to topical imiquimod treatment. Of 13 patients (9 males) with extensive condylomata acuminata (warts) 4 underwent curative circumcision and 9 required extensive ablation. 5 of the latter (3 males) had squamous cell carcinomas. All were managed syndromically as STIs for >18 months. 4 patients had chronic genital ulcers with no discernible cause and very low CD4 counts. These ulcers healed completely after commencement of anti-retroviral treatment. Onemale with penile abscesses and multiple urinary fistulas had trichomonas vaginalis repeatedly isolated and responded to a prolonged course of metronidazole. Other diagnoses included severe tinea cruris (4), lichen planus chronicus (2), papular pruritic eruptions (PPE) (1), penile pearly papules (PPP) (1), vitiligo (1). Conclusion: We need to develop expertise in the management of patients who do not respond to syndromic STI/GUS treatment and develop clear referral pathways to secondary and tertiary care centres with adequate facilities and investigative capacity for timeous diagnosis and intervention. This is particularly urgent in the context of HIV/AIDS.