Background Data regarding long-term outcomes following percutaneous cholecystostomy (PC) are limited, and comparisons to cholecystectomy (CCY) are lacking. We hypothesized that chronic disease burden would predict 1-year mortality following PC, and that outcomes following PC and CCY would be similar when controlling for preprocedural risk factors. Methods We performed a 10-year retrospective cohort analysis of patients with acute cholecystitis managed by PC (n = 114) or CCY (n = 234). Treatment response was assessed by systemic inflammatory response syndrome (SIRS) criteria at PC/CCY and 72 h later. Logistic regression identified predictors of 30-day and 1-year mortality following PC. PC and CCY patients were matched by age, Tokyo Guidelines (TG13) cholecystitis severity grade, and VASQIP calculator predicted mortality (n = 42/group). Results The presence of SIRS at 72 h following PC was associated with 30-day mortality [OR 8.9 (95% CI 2.6–30)]. SIRS at 72 h was present in and 21.4% of all PC patients, significantly higher than unmatched CCY patients (4.7%, p = 0.048). Independent predictors of 1-year mortality following PC were DNR status [19.7 (2.1–186)], disseminated cancer [7.5 (2.1–26)], and congestive heart failure [3.9 (1.4–11)]. PC patients with none of these risk factors had 17.9% 90-day mortality and no deaths after 90 days; late deaths continued to occur among patients with DNR, CHF, or disseminated cancer. At baseline, PC patients had greater acute and chronic disease burden than CCY patients. After matching, PC and CCY patients had similar age (69 vs. 70 years), TG13 grade (2.4 vs. 2.4), and predicted 30-day mortality (5.5 vs. 6.8%). Matched PC patients had higher 30-day mortality (14.3 vs. 2.4%, p = 0.109) and 180-day mortality (28.6 vs. 7.1%, p = 0.048). Conclusions Treatment response to PC predicted 30-day mortality; DNR status, and chronic diseases predicted 1-year mortality. Although the matching procedure did not eliminate selection bias, PC was associated with persistent systemic inflammation and higher long-term mortality than CCY.