Kaposi sarcoma (KS) is a rare angioproliferative malignancy linked to human herpesvirus 8 infection. While systemic therapy is often unnecessary for classic and iatrogenic KS, advanced cases may require chemotherapy. This study aims to evaluate the efficacy and safety of weekly paclitaxel or oral etoposide as second-line treatments for classical and iatrogenic Kaposi sarcoma. We retrospectively analyzed clinicopathological characteristics and treatment outcomes of 32 patients diagnosed with classical and iatrogenic KS at a tertiary cancer center between December 2000 and November 2022. Patients received oral etoposide (50 mg every 3 weeks for 10 days) or weekly paclitaxel (80 mg/m²). The cohort comprised 23 males (71.9%) and 9 females (28.1%), with a mean age of 63 years. Most patients (87.5%) had classical KS, while 12.5% had iatrogenic KS. The objective response rate (ORR) was 75%, with a disease control rate (DCR) of 87.5%. Median progression-free survival (PFS) was 32.1 months, and median overall survival (OS) was 110.2 months. No significant differences in PFS (P = .633) and OS (P = .456) were observed between paclitaxel and etoposide treatments. The treatment regimen was generally well tolerated. Severe hematological toxicities were less frequent, with febrile neutropenia in 1 patient (3.1%), while severe non-hematological side effects included neuropathy in 2 patients (6.2%). Two patients (6.2%) were hospitalized due to complications, with no treatment-related deaths. Weekly paclitaxel and oral etoposide regimens are effective and well-tolerated second-line treatments for classical and iatrogenic Kaposi sarcoma. Given the high ORR and DCR, these therapies represent viable options for patients who progress after initial treatment. Further studies with larger patient populations are needed to confirm these findings.