Pyoderma gangrenosum (PG) has been linked to various underlying systemic diseases; many associations are based on case reports or small case series, including hidradenitis suppurativa. Literature examining systemic therapies according to underlying comorbid condition is limited. The study objective was to investigate comorbid diseases of PG and correlate disease associations with effectiveness of therapeutic interventions. Using Johns Hopkins Medical Institutions medical records, 220 patients had an ICD-9 code of 686.01 for PG between 1 January 2006 and 30 June 2015, of whom 130 patients met rigorous inclusion/exclusion criteria for PG (non-peristomal). The 130 PG patients in our study were 69% female, 58% Caucasian, and 35% African American. Documented comorbid conditions included inflammatory bowel disease (IBD; 35%), rheumatoid arthritis (RA; 12%), hidradenitis suppurativa (HS; 14%), and monoclonal gammopathy (12%). PG patients with HS versus without HS were more likely to be African-American (83% vs. 28%; P < 0.001) and had an earlier mean age of PG onset (38 vs. 48 years; P = 0.02). Strikingly, 53% of female African-American patients with PG onset prior to age 40 had comorbid HS. Comorbid inflammatory bowel disease was observed in 38% of PG patients with RA, 28% of PG patients with HS, and 27% of PG patients with monoclonal gammopathy. Of the 32 patients who received infliximab for active PG, complete ulcer healing was observed in 83% (5/6) of patients with comorbid HS versus 31% (8/26) of patients without HS (Fisher exact P = 0.03). Screening patients for associated systemic disease for multiple related illnesses is essential. Effectiveness of systemic therapy may depend upon the underlying systemic disease; hidradenitis suppurativa may be a specific example.