Background: Fournier’s gangrene (FG) is a rapidly progressive necrotizing fasciitis of the perineum and genital region. Diabetes mellitus is a major predisposing factor that may influence microbial spectrum and antibiotic resistance patterns.

Objective: To compare the clinical profile, microbial spectrum, and antimicrobial resistance in diabetic and non-diabetic FG patients.

Methods: In this prospective observational study at a tertiary care hospital, patients diagnosed with FG over 24 months were categorized into diabetic and non-diabetic groups. Clinical features, risk factors, microbial isolates, and antibiotic susceptibility patterns were recorded. Comparisons were made using appropriate statistical tests.

Results: Of 50 patients, 32 (64%) were diabetic. Mean age was 50.6 years; males comprised 68%. Local trauma (42%) was the most common predisposing factor. Clinical features, including erythema, tenderness, and edema, were common in both groups without significant difference. Polymicrobial infection occurred in 72% of cases. Streptococcus spp. predominated overall, with higher prevalence in diabetics. Pseudomonas spp. were significantly more common in diabetics (p = 0.022), while Enterobacter spp. were seen only in non-diabetics (p = 0.025). High rates of ESBL production and carbapenem resistance were observed among Gram-negative isolates. MRSA was detected in 8 cases.

Conclusion: Clinical presentation of FG is similar in diabetics and non-diabetics; however, microbial profiles differ, with diabetics showing higher Pseudomonas isolation. Rising multidrug resistance warrants early, broad-spectrum empiric therapy with subsequent de-escalation